Molecular Classification of Primary Immunodeficiency PDF

CHAPTER FOUR
Molecular Classification of Primary

Immunodeficiencies of
T Lymphocytes
William A. Comrie*,†, Michael J. Lenardo*,†,1
*Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National
Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
†
Clinical Genomics Program, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda,
MD, United States
1
Corresponding author: e-mail address: mlenardo@niaid.nih.gov
Contents
1. Introduction 100
2. PIDs 101
3. PIDs of T Cell Function 103
3.1 Defects in T Cell Development 104
3.2 Mutations Affecting TCR Signaling 106
3.3 Defects in Costimulatory Pathways 122
3.4 Defects of Cytokine Signaling 126
3.5 Defects in Adhesion, Migration, or Cytoskeletal Organization 131
3.6 Defects in TFs/TF Regulation 139
3.7 Defects in Apoptotic Pathways 142
3.8 Defects in DNA Replication, Accessibility, Repair, and Telomere
Maintenance 146
3.9 Vesicular Trafficking and Protein Sorting 151
3.10 Defects of Ubiquitination 155
3.11 Defects of Glycosylation 155
3.12 Defects in Autophagy and Protein Turnover 158
3.13 Defects in Metabolic Pathways 159
3.14 Altered T Cell Effector Function in Complement Deficiencies 162
3.15 Unknown Mechanism 163
4. Current Challenges/Approaches and Future Considerations 164
References 167
Abstract
Proper regulation of the immune system is required for protection against pathogens
and preventing autoimmune disorders. Inborn errors of the immune system due to
inherited or de novo germline mutations can lead to the loss of protective immunity,
aberrant immune homeostasis, and the development of autoimmune disease, or
Advances in Immunology, Volume 138 2018 Published by Elsevier Inc. 99

ISSN 0065-2776
https://doi.org/10.1016/bs.ai.2018.02.003
100 William A. Comrie and Michael J. Lenardo
combinations of these. Forward genetic screens involving clinical material from patients
with primary immunodeficiencies (PIDs) can vary in severity from life-threatening dis-
ease affecting multiple cell types and organs to relatively mild disease with susceptibility
to a limited range of pathogens or mild autoimmune conditions. As central mediators of
innate and adaptive immune responses, T cells are critical orchestrators and effectors of
the immune response. As such, several PIDs result from loss of or altered T cell function.
PID-associated functional defects range from complete absence of T cell development
to uncontrolled effector cell activation. Furthermore, the gene products of known PID
causal genes are involved in diverse molecular pathways ranging from T cell receptor
signaling to regulators of protein glycosylation. Identification of the molecular and bio-
chemical cause of PIDs can not only guide the course of treatment for patients, but also
inform our understanding of the basic biology behind T cell function. In this chapter, we
review PIDs with known genetic causes that intrinsically affect T cell function with par-
ticular focus on perturbations of biochemical pathways.
1. INTRODUCTION
This theme has been at the centre of all my research…, both because of its intrinsic
fascination and my conviction that a knowledge of sequences could contribute
much to our understanding of living matter.
Frederick Sanger
T lymphocyte cells (T cells) play a central role in the adaptive immune

response, coordinating immune functions comprising both humoral and
cell-mediated responses to a myriad of immunogenic challenges including
infection and cancer. Therefore, understanding how these cells work in
humans requires a detailed molecular approach combining cellular immu-
nology, clinical investigation, and human genetics. Normally, mechanisms
of central and peripheral tolerance limit the response to self, thus preventing
autoimmune disease. These varied and at times conflicting roles require
many levels of control to appropriately modulate T cell-mediated immune
responses. These include regulation of T cell development, maintenance of
quiescence and self-tolerance, initiation and maintenance of T cell activation
in response to cognate antigen, migration to effector sites, effector function,
differentiation, and maintenance of a memory population. Multiple genes
regulate these steps in ways critical to proper immune responses. One
method of identifying important regulators of T cell function is a genetic
approach involving the investigation of individuals with inborn errors of
immunity. These primary immunodeficiencies (PIDs) result in diverse and
overlapping clinical phenotypes including immunodeficiency (susceptibility
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 101
to malignancy or infection), abnormal cellular homeostasis, autoimmunity,

autoinflammation, and allergy. PIDs represent a forward genetic screen of
nature, meaning that a phenotype is first identified—often provoked by
infectious and noninfectious immunological challenges that the patients
encounter—and then the pathophysiological attributes in immunity and
ultimately gene variants that correlate with disease are interrogated. Within
the last decade, the development of inexpensive technologies for sequencing
the DNA of the human genome or exome (the coding portion of the
genome) have allowed for the rapid identification of the genetic variants
underlying various PIDs. This coupled with the vast reach of clinical med-
icine to identify, characterize, and follow longitudinally patient phenotypes
has facilitated a powerful new approach to understand the effect of genotype
variation on human immune function. In this chapter, we will discuss the
biochemical and molecular basis of disease in PIDs caused in whole or in part
by defects in T cell function.
2. PIDs
PIDs are most easily understood when they are caused by highly pen-
etrant single-gene errors. Clinical manifestations of PIDs usually present in
childhood and can be due to either de novo or hereditary mutations with
various Mendelian modes of inheritance (MOIs). Affected genes can be spe-
cifically required for a certain immune response, formation of a single immu-
nological cell type, or may more broadly affect a common cellular process
necessary for proper immunological function. As such, PIDs can present with
an extremely narrow clinical presentation, such as susceptibility to a single
class of pathogen, or with wide-ranging clinical immune phenotypes with
syndromic (nonimmune) features. The variants that cause PIDs are generally
highly deleterious to the function of the encoded protein and, as such, are
relatively rare (<0.1%) within a given population compared to less deleteri-
ous variants. This contrasts with the relatively common variants (0.1%) that
contribute to the susceptibility to more common immunological diseases
such as type 1 diabetes mellitus (T1DM) and inflammatory bowel disease
(IBD). Though the single-gene defects giving rise to PIDs tend to be severe,
there can be significant differences in penetrance (the proportion of individ-
uals with a disease genotype having the corresponding clinical phenotype)
and expressivity (the constellation and severity of clinical symptoms). The
International Union of Immunological Societies Expert Committee for Pri-
mary Immunodeficiencies keeps a continuously updated list of known PID
genes, which, as of writing this review, has a total of 354 immunological dis-
eases with a known genetic cause, accounting for nearly 10% of all single gene
disorders that have been defined (http://www.iuisonline.org).
Despite the relative rarity of PIDs compared to other immunological dis-
orders, there are a multitude of benefits that can be gained by studying the
underlying genetic and biochemical mechanism of PID pathogenesis. First,
it provides an opportunity to gain novel insight into regulation of the
human immune system. Second, it can offer great benefit to the patients
who carry the burden of these disorders. Identification of the causal variant,
MOI, and mechanism of action may provide clinicians with guidance in
selecting a targeted therapy and allows for informed genetic counseling
to the family with critical information relevant to life decisions. Third, we also
gain scientific insights into the molecular pathways that mediate infectious
and autoimmune disease at the population level. Fourth, by genetically
“solving” PIDs, new immune genes have been discovered, new functions
of known genes have been elucidated, and knowing how genes affect human
immunology enables us to better annotate the human genome (Casanova,
Abel, & Quintana-Murci, 2013). Finally, a key benefit of studying PIDs
is understanding the variability of the causal genetic lesions generated by
random mutation in the human population which cannot be derived from
experimental animal models. These experiments of nature can lead to similar
clinical disease caused by completely different genes and demonstrate that
the same gene can cause various clinical phenotypes dependent on the type
of mutation. This can allow for identification of gene functions in the biolog-
ical context of both loss-of-function (LOF) and gain-of-function (GOF)
mutations, thus taking the study of a gene well past where the usefulness of
studying traditional knockout mice ends. Additionally, the constant exposure
of humans to environmental influences and a multitude of infectious agents
can help identify gene function that would not be immediately apparent in
simple inbred mouse models that are housed under specific pathogen-free
conditions.
Pathogenic DNA variants, excluding copy number variation or complete
deletion of the genetic locus, can be broken down into three categories: LOF,
hypomorphic mutations (partial LOF), and GOF. GOF mutations can be fur-
ther divided into two types: increased activity of a traditional function and
gain of a novel function. Fitting into one of these operational categories
are multiple types of DNA variants that include coding variants such as non-
sense, frameshift, canonical splice site mutations, loss of the initiation codon,
larger insertions or deletions, and missense mutations, as well as noncoding
variants in promoter or enhancer regions, that may alter the transcription of

the gene, or intronic variants that may introduce a new splice site. Further
complicating the genetic analysis of PID patients is that a given pathogenic
genetic variant can cause either a dominant or recessive manifestation of dis-
ease, in which one or two alleles must be affected, respectively. Furthermore,
different PIDs with distinct MOI may arise from mutations in the same gene.
Examples of this will be discussed on a case-by-case basis in the following
section. A recessive MOI is generally caused by LOF variants while a dom-
inant MOI can be caused by LOF variants in which one allele is insufficient or
actively interferes with the function of the other allele (haploinsufficiency or
dominant interference, respectively) or by GOF variants. Undoubtedly, PIDs
may be caused by the interaction of multiple genes or by alterations of the
intergenic regions; however, the tools are still being developed to address
those possibilities.
PID patients are typically characterized by their clinical and cellular phe-
notypic presentation prior to any knowledge of their genotype, and this
information can often influence the prioritization of potential causal vari-
ants. For example, variants may affect known PID genes or lie in genes that
have already been associated with a specific biochemical pathway, a partic-
ular cell type, or a given clinical presentation (Bousfiha et al., 2015; Picard
et al., 2015). Currently, there are eight categories of PIDs based upon phe-
notypic classification: immunodeficiencies affecting cellular and humoral
immunity, combined or severe combined immune deficiency (CID/SCID)
with or without associated/syndromic features, antibody deficiencies, dis-
eases of immune dysregulation, defects in phagocyte number/function,
defects in innate immunity, autoinflammatory disorders, and complement
deficiencies. Additionally, there are intriguing somatic mutation-based dis-
orders or autoantibody-induced conditions that mimic PIDs that will not be
discussed here. Because of the pivotal role of T cells in innate and adaptive
immune responses, we will focus in this review on a large variety of PIDs
that result from loss of, or altered T cell function and developmental
T cell defects that range from complete absence of T cells to uncontrolled
effector cell activation.
3. PIDs OF T CELL FUNCTION

In this section, we will discuss T cell-intrinsic PIDs, characterizing
these mutations by the molecular mechanism that is disrupted in each PID
rather than by the associated clinical or cellular phenotype. PIDs affecting
T cell function that are caused by alterations in antigen-presentation cells

(APCs) or other external determinants of T cell development/function
will not be discussed and some have been reviewed elsewhere (Conley
et al., 2009). Importantly, several proteins have roles in multiple pathways
and may be classified in one or more of the functional categories we
define. For simplicity, we will only mention a given protein under a sin-
gle category, but will discuss noted areas of overlap with other categories
when present and OMIM disease identifiers will be provided, where
available.
3.1 Defects in T Cell Development

3.1.1 Thymic Development
Deleterious gene variants that alter thymus formation can affect T cell
development. Of the known genes associated with thymic development,
four cause a recognized PID. Haploinsufficiency of the T-box transcrip-
tion factor 1 (TBX1), caused by a 1.5–3.0 Mb deletion at chromosome
22q11.2, causes DiGeorge syndrome (OMIM 188400), which involves
thymic hypoplasia and T cell deficiencies ranging from relatively mild
to a SCID-like phenotype in athymic individuals (Davies, 2013; Jerome
& Papaioannou, 2001; Lischner & Huff, 1975; Yagi et al., 2003). Muta-
tions in the sema domain, immunoglobulin domain (Ig), short basic
domain, secreted (semaphorin) 3E protein (SEMA3E) are required for
proper angiogenesis. Chromodomain-helicase-DNA-binding protein 7
(CHD7), the chromatin remodeling protein and likely transcription factor
(TF), has an essential role in tissue patterning. Mutations in either SEMA3E
or CHD7 cause autosomal dominant CHARGE syndrome and are associ-
ated with thymic hypoplasia or aplasia and a variety of associated T cell
defects (OMIM 214800) (Bajpai et al., 2010; Gu et al., 2005; Jongmans
et al., 2006; Lalani et al., 2004; Martin, Sheldon, & Gorski, 2001;
Van Nostrand et al., 2014; Wong, Scholvinck, Lambeck, & van
Ravenswaaij-Arts, 2015). Mutations in the master regulator of thymic epi-
thelial cell formation, Forkhead Box N1 (FOXN1), cause an autosomal
recessive SCID disorder mimicking that of Nude mice with a severe T cell
immunodeficiency due to abrogated thymus formation (OMIM 601705)
(Frank et al., 1999; Pignata et al., 1996; Romano et al., 2013; Rota &
Dhalla, 2017). In these cases of athymia, thymic transplant can correct the
immune defect, since there is no underlying intrinsic defect in T cell devel-
opment (Markert et al., 2007, 2011).
3.1.2 VDJ Recombination

During development of T and B cells, the germline locus of the T cell anti-
gen receptor (TCR) and B cell antigen receptor (BCR) undergo genetic
recombination of the V, D, and J loci to form unique protein-coding genes
for each of the receptor chains. Since only one or two of these alleles are
completed in each cell, this generates a diverse repertoire of clonal lympho-
cytes harboring different antigen receptor specificities needed for broad
immune protection. As such, severe defects in genes required for VDJ
recombination lead to a T/B/natural killer (NK)+ SCID. Hypomorphic
mutations in several of these genes lead to defects in selection, but allow
some B and T cells to develop, but with reduced or autoreactive repertoires,
forming the basis for Omenn syndrome and combined cellular and humoral
immune defects with hranulomas (CCHIDG). The exact course of disease
depends on the severity of the mutation, and, in the case of hypomorphic
mutations that are incompletely penetrant, other factors such as genetic
background and infectious history. Biallelic LOF and hypomorphic muta-
tions in both recombination activating gene (RAG) 1 and 2, which together
form the catalytic core of the RAG DNA cleavage complex, have been
described to cause all three diseases: SCID (OMIM 601457), Omenn
(OMIM 603554), and CCHIDG (OMIM 233650) (Schuetz et al., 2008;
Schwarz et al., 1996; Villa et al., 1998). Following DNA cleavage, the
Artemis/DNA-dependent protein kinase, catalytic subunit (DNA-PKcs)
complex forms a key 50 -30 exonuclease that is required for nonhomologous
end-joining (NHEJ)-mediated DNA repair. This exonuclease activity is
important for the removal of DNA hairpins created by the RAG complex
(Ma, Pannicke, Schwarz, & Lieber, 2002; Ma, Schwarz, & Lieber, 2005).
Mutations in Artemis and DNA-PKcs cause SCID with increased sensitivity
to non-RAG-initiated double-strand breaks, such as those caused by radiation
(OMIM 602450 and 615966, respectively) (Moshous et al., 2001; van der
Burg et al., 2009). Artemis mutations can also cause Omenn syndrome
(Ege et al., 2005). During recombination, after exonuclease activity, the
double-strand break must be repaired to link VDJ segments to create open
reading frames for immunoreceptor proteins. NHEJ factor 1 (NHEJ1), which
was first identified via genetic screening of SCID patients, and DNA ligase IV
forms a complex necessary for NHEJ following RAG-mediated double-
strand breaks (Ahnesorg, Smith, & Jackson, 2006; Grawunder, Zimmer,
Fugmann, Schwarz, & Lieber, 1998). Mutations in both proteins cause
radiosensitive SCID with syndromic features (OMIM 611291 and 606593,
respectively) (Buck et al., 2006; van der Burg et al., 2006). Thus, mutations
in various proteins involved in the cutting, processing, and rejoining of

double-strand breaks during T and B cell development give rise to an over-
lapping family of disorders. One interesting question that remains is why there
is such a wide range of clinical phenotypes associated with RAG mutations;
one might infer that these proteins have multiple roles in the metabolism of
the genome or other cellular functions (Notarangelo, Kim, Walter, & Lee,
2016). Complete LOF mutations in RAG are simpler to understand, as these
result in complete lack of T and B cell development, resulting in loss of adap-
tive immunity. Disease caused by hypomorphic mutations are more complex,
because these variants result in decreased T and B cell selection as well as lead
to the loss of regulatory cell populations and expansion of autoreactive cell
clones in a lymphopenic environment. This likely accounts for the diverse
autoimmune phenotypes associated with Omenn syndrome. Meanwhile, less
severe hypomorphic mutations can lead to mild defects in T and B cell selec-
tion allowing a diverse repertoire, lymphadenopathy, and milder immunode-
ficiencies developed later in life, such as CCHIDG.
3.2 Mutations Affecting TCR Signaling

Several PIDs have been associated with deleterious variants leading to aber-
rations of proximal TCR-mediated signaling (Fig. 1) (Notarangelo, 2013).
Importantly, many of these mutations lead to general loss of the T cell com-
partment and consequent deficits in immunity in affected individuals, but
can also lead to autoimmune conditions through loss of Tregs, altered thy-
mic selection leading to formation of autoreactive T cells, or altered/
enhanced TCR signaling that cause aberrant T cell activation, effector func-
tion, and memory formation.
3.2.1 TCR Chains

T cells recognize antigen through binding of the TCR to antigenic pep-
tides presented by major histocompatibility complex (MHC) molecules
on APCs. The TCR is a multimeric complex consisting of the peptide–
MHC binding chains TCRα and TCRβ associated with signaling chains
comprising cluster of differentiation (CD)3ε, CD3δ, CD3γ, and CD3ζ in
a 1:1:2:1:1:2 ratio. Deleterious variants affecting each of these proteins,
except TCRβ, have been associated with autosomal recessive SCID and
autoimmune disease.
Homozygous LOF TCRα mutations cause loss of TCRαβ-expressing
T cells and features of both autoimmunity and immunodeficiency (OMIM
615387). Patients, mostly children, are susceptible to recurrent respiratory
Fig. 1 Primary immune deficiencies in T cell signaling and actin regulatory pathways. Schematic of signaling downstream of the T cell recep-
tor, costimulatory, and adhesion molecules. Mutations in molecules shaded in red are known to cause a primary immune disease.
tract infections, varicella and Epstein–Barr virus (EBV) infections, otitis

media, candidiasis, diarrhea, and failure to thrive and can variably develop
hypereosinophila, autoantibodies, eczema, vitiligo, autoimmune hemolytic
anemia, lymphadenopathy, and organomegally (Morgan et al., 2011). Loss
of either CD3ε (OMIM 615615) or CD3δ (OMIM 615617) results in the
selective loss of T cells, and patients present with diminished class-switched
immunoglobulins, recurrent respiratory and ear infections, along with
recurrent gasteroenteritis (Dadi, Simon, & Roifman, 2003; Dave et al.,
1997; de Saint Basile et al., 2004; Gil et al., 2011; Soudais, de Villartay,
Le Deist, Fischer, & Lisowska-Grospierre, 1993). Loss of CD3ζ (OMIM
610163) results in erythroderma, diarrhea, pulmonary infections with sus-
ceptibility to pseudomonas, herpes simplex virus (HSV), and candida infec-
tions of the mouth and skin (Rieux-Laucat et al., 2006). Finally, loss of
CD3γ (OMIM 615607) can result in combined immunodeficiencies and
autoimmunity including susceptibility to viral, bacterial, and fungal infec-
tions, low immunoglobulin G (IgG) levels, autoantibodies, autoimmune
hemolytic anemia, and enterocolitis (Arnaiz-Villena et al., 1992; Recio
et al., 2007). As noted earlier, there is considerable variation in cellular phe-
notypes depending on the affected CD3 chain as well as variable expressiv-
ity within a given genetic defect. For instance, some mutations in CD3δ
result in complete loss of T cells while others leave γδ+ T cell development
intact. This may be due to the degree that different mutations affect CD3δ
association with either αβ or γδ chains. Additionally, in multiplex kindreds
with identical CD3γ mutations, different mutation-bearing patients can
develop either mild or severe disease, likely indicating the presence of mod-
ifying genetic variants or the influence of infectious history. This degree of
intrakindred variable expressivity is also reminiscent of other disorders such
as hypomorphic RAG mutations discussed earlier and could be influenced
by the individual T cell population that is selected in the thymus. In general,
CD3δ mutations are more deleterious than CD3γ mutations (Dadi et al.,
2003; Dave et al., 1997; Recio et al., 2007). The differences possibly reflect
varying signaling or complex formation requirements for individual chains
and may be predisposed by the severity of the causal variant, with point
mutants that disrupt recruitment of downstream signaling molecules poten-
tially being less deleterious than complete protein deficiency.
3.2.2 CD8α
An autosomal recessive disease of recurrent bacterial and viral lung infections
is caused by biallelic deleterious variants in CD8α, encoding the CD8α chain
of the coreceptor for TCR interaction with class I MHC (OMIM 608957).
The CD8 and CD4 coreceptors are important for TCR signaling by binding
the constant portion of the MHCI and MHCII molecules, respectively, and
recruiting the lymphocyte-specific protein tyrosine kinase (Lck) to the TCR
complex where it initiates downstream signaling by phosphorylating CD3
chains and downstream kinases (Fig. 1). Interestingly, CD8α deficiency
may have incomplete penetrance. For example, two healthy siblings of
one patient have been identified as being homozygous for the same disease
allele (de la Calle-Martin et al., 2001; Mancebo et al., 2008). The reason for
this remains to be determined.
3.2.3 CD45
An autosomal recessive Tlow/NK+/B+ SCID phenotype (OMIM 608971)
is caused by biallelic LOF mutations in the gene encoding the protein
phosphatase CD45. Patients exhibit a combination of rash, fever, hepatos-
plenomegaly, diffuse lymphadenopathy, pneumonitis, pancytopenia, B cell
lymphoma, and neonatal cytomegalovirus (CMV) infections. Patient immu-
nophenotyping reveals very low αβ-positive T cells with normal or elevated
NK cells and normal or elevated B cells with defective germinal center forma-
tion and low Ig levels. The diffuse lymphadenopathy was B cell dependent.
Importantly, patient T cells failed to respond to mitogens (Kung et al.,
2000; Roberts et al., 2012; Tchilian et al., 2001). Interestingly, cd45/ mice
also show arrested T cell development at the transition from double positive
to single positive cells, phenocopying Lck-deficient mice. This appears to
be a gene dosage effect, because heterozygous mice have a moderate
decrease in single positive T cells compared to controls (Kishihara et al.,
1993). Further analysis revealed that in vitro B cell activation in response
to surface Ig-crosslinking to be defective in knockout cells as well as an
accumulation of pro-B cells, suggesting a B cell-intrinsic role for CD45
(Fleming, Milne, & Paige, 2004). These data suggest a possible unappre-
ciated B cell defect in CD45-deficient patients, though this has not been
previously described. In addition to the autosomal recessive disease, hetero-
zygous CD45 splice site mutations are associated with the development of
familial multiple sclerosis, though this association needs further investiga-
tion, and heterozygous LOF mutations occur with less than expected fre-
quency, possibly indicating an unrealized clinical condition associated with
CD45 haploinsufficiency (ExAC) (Jacobsen et al., 2000).
CD45 is a protein phosphatase known to positively regulate TCR
signaling by removing an inhibitory phosphate at Y505 on Lck (Burns,
Sakaguchi, Appella, & Ashwell, 1994; Koretzky, Kohmetscher, & Ross,

1993). It should be noted that CD45 can also remove activating phosphates
both within Lck and the TCR, and Lck isolated from cd45/ thymocytes
show increased kinase activity, indicating that the exact consequences
of CD45 deficiency on signaling dynamics are complicated and not fully
understood (D’Oro & Ashwell, 1999; Furlan, Minowa, Hanagata,
Kataoka-Hamai, & Kaizuka, 2014). CD45 also promotes NK cell cytokine
production and the inhibition of JAK/STAT signaling (Hesslein, Takaki,
Hermiston, Weiss, & Lanier, 2006; Irie-Sasaki et al., 2001). Interestingly,
decreased CD45 expression and CD45 mutations are associated with T and
B acute lymphoblastic leukemia where its absence contributes to increased
JAK/STAT signaling with the consequence of sensitivity of the trans-
formed cells to JAK inhibitors (Nakamura et al., 2001; Porcu et al.,
2012; Raponi et al., 2015). This is of particular interest as one of the
described SCID cases developed splenomegaly and lymphadenopathy
dependent on a B cell lymphoma. Thus, dysregulation of the JAK/STAT
pathway may also be a feature of CD45 deficiency. Further analysis of
patients with CD45 deficiency will likely yield interesting insights into
the B and NK cell defects and the role of elevated JAK/STAT signaling
in the patient phenotypes.
3.2.4 Lck
Lck is a tyrosine kinase that is recruited to the cytoplasmic tails of the
CD4 and CD8 coreceptors and is thus recruited to the TCR complex upon
coreceptor binding to MHC. Active Lck directly phosphorylates the
immunoreceptor tyrosine-based activation motifs (ITAMs) on the CD3
chains of the TCR complex. This is the earliest known phosphorylation
event upon TCR engagement and is essential for the antigen-mediated acti-
vation of T cells. Lck-dependent ITAM phosphorylation results in the
recruitment of zeta-chain-associated protein kinase 70 (ZAP-70) through
its Src homology 2 (SH2) domain and its subsequent phosphorylation and
activation by Lck (Salmond, Filby, Qureshi, Caserta, & Zamoyska, 2009).
Biallelic LOF mutations in LCK lead to an autosomal recessive PID
(OMIM 615758). In 2012, a single 15-month-old baby was discovered to
harbor a homozygous Lck missense mutation (L341P), which results in pro-
duction of an unstable and inactive Lck protein. TCR signaling was absent
in the patient and in a model system of Lck-deficient Jurkat T cells recon-
stituted with the Lck variant (L341P) (Hauck et al., 2012). The patient
suffered from diarrhea and failure to thrive, recurrent upper respiratory
infections, multiple modular skin lesions characterized by infiltration of
macrophages, and CD3+ T cell as well as neutrophil necrosis. Additionally,

the patient had autoimmune cytopenias due to autoantibody formation.
Immunophenotyping showed reduced CD4+ and CD8+ T cells with the
remaining CD8 cells manifesting a central memory or exhausted memory
(TEMRA) cellular phenotype. Three additional patients were identified
with T cell-specific immunodeficiencies, two with loss of Lck exon 7
and reduced protein expression, and one with normal Lck protein levels
but reduced kinase activity. In each of these patients, the decrease in Lck
expression/activity correlated with reduced signaling and cellular activation
following TCR stimulation, suggesting the presence of hypomorphic muta-
tions, though the causal variant was not identified in any of these patients,
leaving them without genetic confirmation of Lck deficiency (Goldman
et al., 1998; Hubert et al., 2000; Sawabe et al., 2001). Of these three patients,
the one with defective kinase activity was largely asymptomatic at 66 years
old, but showed reduced CD4+ T cell numbers with an increased memory
phenotype and unaffected CD8+ T cells. By contrast, the two patients with
Lck lacking exon 7 showed selective CD4+ T cell loss accompanied by
lymphadenopathy, low IgG, diarrhea, failure to thrive, candidiasis, and sep-
sis. Together, these data suggest that Lck deficiency may cause a selective
T cell defect, preferentially affecting CD4+ T cells and resulting in decreased
or absent TCR signaling. The cellular and clinical phenotype likely depends
on the causal mutation. Those that permit a significant level of residual Lck
kinase activity likely cause a less severe cellular and clinical phenotype. On
the other hand, severely deleterious variants likely limit thymic output
allowing for lymphopenia-induced proliferation and expansion of self-
reactive T cells that may account for the increased proportion of TEMRA
cells in some patients. Interestingly, the L341P mutation positive cells did
not undergo restimulation-induced cell death (RICD) which, when com-
bined with the requirement of Lck signaling for apoptosis mediated by the
tumor necrosis factor receptor superfamily member 6 (FAS) receptor, may
account for the observed lymphadenopathy, though establishing such a con-
clusion requires further investigation (Akimzhanov & Boehning, 2015).
Currently, only biallelic null or hypomorphic Lck mutations have been
associated with a PID. Because Lck is closely regulated and maintained in an
inactive state through phosphorylation of Y505, there remains the possibility
of a dominant PID caused by either dominant-interfering variants, such as
K273R, or GOF mutations, such as mutations of Y505. This is exemplified
by the apparent oncogenicity of Lck activating mutations and the presence
of such mutations in a T cell leukemia cell line (Laham, Mukhopadhyay, &
Roberts, 2000; Wright, Sefton, & Kamps, 1994).
3.2.5 ZAP-70
ZAP-70 is a tyrosine kinase critical for TCR signaling. It is first recruited to
phosphorylated ITAMs on CD3ζ and is subsequently phosphorylated and
activated by Lck. Once activated, it phosphorylates linker for activation
of T cells (LAT) and SH2 domain containing leukocyte protein of
76 kDa protein (SLP-76), both critical adaptor molecules in the TCR sig-
naling pathway (Chan, Iwashima, Turck, & Weiss, 1992; Wang et al., 2010;
Zhang, Sloan-Lancaster, Kitchen, Trible, & Samelson, 1998). Biallelic LOF
mutations in ZAP-70 cause an autosomal recessive disease characterized as a
selective deficiency of CD8+ T cells due to abnormal thymic selection
(OMIM 269840) (Arpaia, Shahar, Dadi, Cohen, & Roifman, 1994; Elder
et al., 1994). Although the number of CD4+ T cells is normal in ZAP70-
deficient patients, their function is not. They exhibit abnormal calcium flux
in response to TCR engagement, demonstrating defective TCR signaling
(Chan et al., 1994). Clinically, ZAP70-deficient patients present early in life
with a history of recurrent infections including viral lung disease, candidiasis,
diarrhea, panhypogammaglobulinemia, and silent brain infarcts (Akar et al.,
2015; Arpaia et al., 1994; Chan et al., 1994; Elder et al., 1994; Liu et al.,
2017). Hypomorphic mutations with some residual kinase activity can result
in a milder phenotype with late-onset immunodeficiency associated with
skin and lung infections. These hypomorphic ZAP-70 patients have mod-
estly reduced T cell counts and reduced TCR-dependent signaling (Picard
et al., 2009a).
An additional autoimmune syndrome has recently been described due to
the unique combination of coinherited activating and hypomorphic muta-
tions in ZAP-70 (OMIM 617006) (Chan et al., 2016). The first of two sib-
lings born to nonconsanguineous parents developed nephrotic syndrome,
blistering skin disease, autoantibodies to clotting factor VIII resulting in
bruising and hemarthrosis, and inflammatory colitis. The second sibling
developed generalized bullous pemphigoid and failure to thrive due to
inflammatory colitis. In both cases, there was no evidence of altered T cell
numbers or immunodeficiency; however, successful hematopoietic stem cell
transplantation (HSCT) proved curative. Both patients possessed compound
heterozygous mutations in the ZAP-70 SH2 and kinase domains. The SH2
mutant did not associate with CD3ζ and resulted in diminished signaling
while the kinase domain mutant resulted in loss of autoinhibition and
enhanced ZAP-70, SLP76, and LAT phosphorylation after TCR stimula-
tion. This example is particularly interesting because the R360P mutation
in the catalytic domain enhanced kinase activity but was not capable of
causing a dominant disease by itself (the single mutation positive sister and
father were phenotypically normal). Apparently, the absence of WT protein
was necessary to allow the activating variant to induce disease, possibly
through preferential recruitment to CD3ζ in the presence of the SH2 variant
protein. It is possible that a more strongly activating mutation may cause a
similar disease in an autosomal dominant MOI.
3.2.6 RhoH
Ras homologue family member H (RhoH) is a hematopoietic-specific small
guanosine triphosphate hydrolase (GTPase), which, due to loss of amino
acid residues conserved in enzymatically active GTPases, can bind but
not hydrolyze GTP. Hence, it is generally considered to be constitutively
active (Li et al., 2002). A mutagenesis screen demonstrated that RhoH
was an essential negative regulator of the integrin LFA-1 (Cherry, Li,
Schwab, Lim, & Klickstein, 2004). Studies in rhoh/ mice showed that
RhoH is essential for T cell positive selection by directing the localization
of Lck and ZAP-70 to the immunological synapse (IS) as well as promoting
Lck’s interaction with and phosphorylation of CD3ζ-inducing downstream
signaling events (Chae, Siefring, Hildeman, Gu, & Williams, 2010; Dorn
et al., 2007; Gu et al., 2006). The interaction of ZAP-70 with RhoH is
mediated through a pseudo-ITAM motif in RhoH and influenced by
Lck activity. Interestingly, RhoH has opposite effects on Ras-related protein
1 (Rap1) and downstream integrin activation depending on the stimulus
with RhoH upregulating TCR-mediated signaling and downregulating
CXCR4-dependent signaling, possibly through the regulation of ZAP-70
localization (Baker et al., 2012).
Two siblings from a single consanguineous family have been described
with homozygous nonsense mutations in RhoH (Crequer et al., 2012).
T cells from the patients show reduced ZAP-70 phosphorylation, both at
baseline and upon TCR engagement. This almost completely abrogates
T cell proliferation in response to TCR stimulatory antibodies. In addition,
while these patients were not T cell lymphopenic, in contrast to rhoh knock-
out mice, they did have reduced naı̈ve T cells and enhanced T cell memory
and TEMRA populations, possibly as a consequence of lymphopenia-
induced proliferation. As in the mice, RhoH deficiency alters thymic
selection as patients display abnormal Vαβ repertoires. Despite the profound
signaling defect and loss of naı̈ve T cells, the patients’ clinical phenotype was
remarkably restricted, presenting with epidermodysplasia verruciformis, a
rare disorder characterized by increased susceptibility to ß-papillomaviruses.
However, one patient also presented with bronchopulmonary disease and

Burkitt lymphoma. This may be B cell intrinsic because hypermutation
of RhoH has been previously associated with B cell lymphomas in otherwise
healthy individuals (Pasqualucci et al., 2001).
3.2.7 Itk
Interleukin-2-inducible T cell kinase (Itk) is a Tec family kinase that is
recruited to sites of TCR activation by binding PtdIns(3,4,5)P3 (PIP3)
through its pleckstrin homology (PH) domain. Once recruited, Itk interacts
with the SLP76/LAT complex and is phosphorylated and activated by Lck.
Following Lck-mediated phosphorylation, Itk then mediates its own
autophosphorylation and that of its downstream target phospholipase C,
gamma 1 (PLCγ) (Andreotti, Schwartzberg, Joseph, & Berg, 2010). Itk activ-
ity is required for T cell activation, effector function, and differentiation
through its phosphorylation of PLCγ and downstream diacylglycerol
(DAG) and calcium (Ca2+)-mediated signaling. Biallelic LOF mutations in
Itk result in a fatal EBV-associated lymphoproliferative disease associated with
increased risk of mononucleosis, Hodgkin’s lymphoma, lymphadenopathy,
splenomegaly, hypogammaglobulinemia, progressive CD4+ T cell loss, recur-
rent infections, autoimmune disorders, and cytopenias (OMIM 613011)
(Ghosh, Bienemann, Boztug, & Borkhardt, 2014; Huck et al., 2009; Linka
et al., 2012; Stepensky et al., 2011). Patient cells and patient-associated
Itk variants induce mild defects in Ca2+ flux downstream of TCR activa-
tion. Itk deficiency likely results in diminished CD8+ T cell ability to kill
EBV-infected B cells leading to the narrow clinical phenotype. Interest-
ingly, both Itk deficiency and MAGT1 deficiency, as discussed later, result
in diminished PLCγ activity and a selective susceptibility to EBV infection.
These two disorders also share a CD4+ T cell lymphopenia, suggesting Itk
and PLCγ are important for CD4+ T cell selection, activation, and/or long-
term survival.
3.2.8 Disorders of Phosphoinositide Signaling (PIK3CD, PIK3R1,

and PTEN)
Phosphoinositide signaling is regulated by specific phosphoinositide
kinases and phosphatases activated downstream of antigen receptors,
coreceptors, and G protein-coupled receptors (GPCRs). These proteins
are critical for the regulation of multiple immune functions, including
T cell activation and migration, and have been associated with a family
of related primary immune disorders (Lucas, Chandra, Nejentsev,

Condliffe, & Okkenhaug, 2016).
PIK3CD encodes for phosphoinositide 3-kinase delta (PI3Kδ or P110δ),
the leukocyte-specific class 1 PI3K capable of phosphorylating PtdIns(4,5)P2
(PIP2) to produce PIP3 in response to activating receptors (Vanhaesebroeck
et al., 1997). PIP3, in turn, recruits protein kinase B (Akt) through its PH
domain, leading to its activation and downstream signaling to multiple effec-
tor pathways, including the mechanistic target of rapamycin (mTOR) path-
way (Vanhaesebroeck, Stephens, & Hawkins, 2012). In 2013, two groups
described an autosomal dominant disease caused by heterozygous activating
mutations in PI3Kδ (OMIM 615513) (Angulo et al., 2013; Lucas et al.,
2014a). These mutations lead to a CID characterized by defects in both
T cells and B cells leading to frequent chest infections and bronchiectasis,
viral infections (herpes, EBV, and CMV), as well as mucosal lymphoid
aggregates, lymphadenopathy, decreased naı̈ve T cells, and increased termi-
nally differentiated effector T cells. The elucidation of the molecular and
genetic mechanism of this condition defined a new disease, called “p110δ
Activating mutation causing Senescent T cells, Lymphadenopathy, And
Immunodeficiency” (PASLI) disease or “Activated PI3Kδ Syndrome”
(APDS). A large cohort study has since shown that there is considerable clin-
ical variability with a mixture of autoimmunity, immunodeficiency, develop-
mental delay, and susceptibility to lymphoma (Coulter et al., 2017). Patient
mutations resulted in enhanced activation of Akt and mTOR signaling, both
at baseline and upon antigen stimulation. This results in enhanced effector
function, as measured by IFNγ production and glycolytic function. Interest-
ingly, patient cells from peripheral blood mononuclear cells (PBMCs) did not
proliferate as efficiently, and had increased RICD, presumably due to the
presence of increased effector memory and senescent TEMRA cells. Rapa-
mycin treatment was able to partially rescue naı̈ve T cell percentages and
decreases terminally differentiated effector cells, providing proof that pharma-
cological inhibition of the affected pathway may have great clinical benefit to
these patients. Moreover, a specific enzymatic inhibitor of p110δ is showing
great promise in a clinical treatment trial of PASLI patients (Rao et al., 2017).
A single patient has been described with biallelic PIK3CD LOF
mutations leading to a disease characterized by hypogammaglobulinemia,
sinopulmonary infections, and septic arthritis (Lucas et al., 2016). This
may more closely phenocopy the knockout mouse that shows reduced
activation of B and T cells following antigen receptor engagement than
the activating mutations do (Okkenhaug et al., 2002).
The PIK3R1 gene encodes several different regulatory subunits (p85α/

p55α/p50α) of class I PI3Ks by utilizing different transcriptional start sites.
The regulatory subunit p85α, the main subunit known to bind PI3Kδ, con-
trols PI3K activation in three ways: by inhibiting degradation of the catalytic
subunit, inhibiting the baseline catalytic activity, and by aiding in the local-
ization of the catalytic subunit to the plasma membrane upon TCR engage-
ment (Lucas et al., 2016). Autosomal dominant mutations in PIK3R1 have
been associated with two separate diseases. The first, short stature, hyper-
extensibility, hernia, ocular depression, Rieger anomaly, and teething delay
(SHORT) syndrome, is a developmental disorder with no known immuno-
logical component (OMIM 269880). Missense, nonsense, and frameshift
mutations have been associated with SHORT syndrome, with several char-
acterized mutations/patient samples showing enhanced baseline pAkt sig-
naling and reduced insulin-induced Akt phosphorylation. Whether this
represents a conditioned tachyphylaxis or a reduced ability of p85α to medi-
ate the recruitment and activation of PI3K remains to be seen (Chudasama
et al., 2013; Chung & Gibson, 2014; Dyment et al., 2013; Thauvin-Robinet
et al., 2013). The second disease is characterized by varying degrees of auto-
immunity, immunodeficiency, malignancy, growth retardation, and neuro-
developmental delay (OMIM 616005) (Elkaim et al., 2016). In all cases,
heterozygous splice site mutations in the acceptor or donor sites surrounding
exon 11 result in exon skipping and loss of amino acids 434–475 in the inter-
SH2 domain. This domain is critical for negative regulation of PI3K catalytic
activity. The resulting protein is still capable of stabilizing and recruiting the
catalytic subunit, but no longer maintains it in an inactive state in the absence
of a stimulatory event (Lucas et al., 2016). Patients exhibit sinopulmonary
infections, likely due to B cell deficiency associated with hyper-IgM syn-
drome, conjunctivitis, autoimmunity (arthritis, IBD, thrombocytopenia,
lymphadenopathy, and splenomegaly), and short stature (Elkaim et al.,
2016; Lucas et al., 2014b; Petrovski et al., 2016). On a cellular level these
patients, like PI3Kδ patients, exhibit increased pAkt and mTOR activation,
both at baseline and following TCR stimulation (Deau et al., 2014; Lucas
et al., 2014b; Petrovski et al., 2016). This is again accompanied by loss of
naı̈ve and expansion of terminally differentiated and senescent T cells. Inter-
estingly, there is an overlap in the clinical features of both dominant PIK3R1
disorders as short stature and poor growth are characteristic of both diseases,
but whether any single mutation can lead to a combined clinical presentation
remains to be seen. Rapamycin (sirolimus) or a specific p110δ may be effec-
tive in ameliorating the clinical phenotype.
Interestingly, complete absence of p85α, due to a homozygous stop

codon, results in decreased p110δ protein expression in all immunological
cell types tested, but caused only a selective loss of the B cell lineage,
suggesting that other PI3Ks may substitute in during T cell development
(OMIM 615214) (Conley et al., 2012).
Specific kinase-activating mutations in PIK3CD and PIK3R1 result in
overt activation of the PI3K pathway by upregulating PIP3 production.
A similar increase in PIP3 is observed when the PIP3 phosphatase, phos-
phatase and tensin homologue (PTEN), is lost. Inactivating mutations
in PTEN have long been associated with cancer cell growth, including
growth of the Jurkat T leukemia cell line. Recently, a PID caused
by PTEN mutations has been described (OMIM 601728) (Hollander,
Blumenthal, & Dennis, 2011; Song, Salmena, & Pandolfi, 2012). In
screening patients with similar clinical manifestations to PIK3CD GOF
and PIK3R1 LOF, Tsujita et al. identified two patients with heterozygous
de novo LOF mutations in PTEN. These patients had recurrent Staphy-
lococcus infection, pancytopenia, pneumonia and respiratory tract infec-
tions, hepatosplenomegaly, lymphadenopathy, an inverted CD4+/
CD8+ ratio, decreased naı̈ve T cell numbers, and reduced numbers of
memory and class-switched B cells (Tsujita et al., 2016). Importantly,
patient cells showed reduced PTEN expression and enhanced pAkt and
mTOR signaling, thus suggesting functional haploinsufficiency. Interest-
ingly, autosomal dominant LOF mutations have already been associated
with several genetic disorders, though only rarely with defined immuno-
logical phenotypes, ex. Cowden’s syndrome (CS, OMIM 158350)
(Browning, Chandra, Carbonaro, Okkenhaug, & Barwell, 2015; Eng,
2003; Ruschak, Kauh, & Luscombe, 1981). Importantly, in the study
by Tsujita et al., one patient had macrocephaly and mental retardation
while the second had mild mental retardation, which are clinical symp-
toms of CS, possibly indicating that these are variable clinical phenotypes
of the same genetic disorder. Fitting with this, two CS patients with no
overt immunological phenotype showed enhanced PI3K pathway activa-
tion in T cells. Interestingly, there is little correlation between mutation
location/type and clinical manifestation, suggesting highly variable clin-
ical expressivity for PTEN haploinsufficiency whose cause is not currently
understood. As in the case of PIK3R1 and PIK3CD disorders, sirolimus
or p110δ inhibitors likely represent targeted therapeutic options for
PTEN haploinsufficiency-associated diseases (Schmid et al., 2014;
Squarize, Castilho, & Gutkind, 2008).
3.2.9 ORAI-1 and STIM1 (Disorders of Ca2+ Flux)

Following PLCγ activation and cleavage of PIP2 to DAG and inositol
triphosphate (IP3), IP3 binds to IP3 receptors on the endoplasmic reticu-
lum (ER) leading to release of Ca2+ from endoplasmic stores. This triggers
the release of Ca2+ from the EF-hand of stromal interaction molecule 1
(STIM1), its conformational change, and oligomerization. Activated STIM1
then induces the influx of extracellular Ca2+ by activating the calcium release-
activated calcium (CRAC) channel protein 1 (ORA-I), located on the
plasma membrane (Vig et al., 2006). The influx of Ca2+ through activated
CRAC channels acts as a key second messenger in TCR signaling (Feske,
Skolnik, & Prakriya, 2012; Soboloff, Rothberg, Madesh, & Gill, 2012).
Hence, the proper function of both STIM1 and ORAI-1 channels is essential
for regulation of Ca2+ signaling. Interestingly, both autosomal recessive
and autosomal dominant diseases can arise due to mutations in STIM1 and
ORAI-1 with similar clinical features.
Biallelic LOF variants in ORAI-1 cause a SCID-like autosomal recessive
disease with syndromic features including muscle weakness and dysplastic
dental enamel (OMIM 612782) (Feske et al., 1996, 2006; McCarl et al.,
2009). Two patients born to consanguineous parents presented within
2 weeks of birth with failure to thrive, rotavirus infection, stomatitis and
aphthous ulcers, mycobacterial infections, sepsis, muscular hypotonia, and
intermittent fever. While T cell and NK cell counts were normal, indicating
lymphocyte ontogeny, patient T cells largely failed to respond to stimu-
lation through the TCR or with phorbol myristate acetate and ionomycin
(PMA/I), showing defective proliferation, cytokine production, and
NF-AT activation (Feske et al., 1996). Patients carried a R91W substitution
in ORAI-1 that caused a loss of extracellular Ca2+ influx following normal
ER store release. This was rescued with reconstitution with wild-type (WT)
ORAI1. Interestingly, heterozygous individuals showed a decreased cal-
cium flux, suggesting a gene dosage effect (Feske et al., 2006). Identification
of additional patients has expanded the clinical phenotype to include chronic
diarrhea, candidiasis, pneumonia, pyelonephritis, toxoplasma encephalitis,
and cytomegalovirus infection with one patient developing autoimmune
neutropenia and thrombocytopenia (McCarl et al., 2009).
An autosomal dominant disease due to mutations in ORAI-1 primarily
affecting muscle tissue with similarities to Stormorken syndrome has been
described (OMIM 615883) (Endo et al., 2015; Garibaldi et al., 2017;
Nesin et al., 2014). The patient phenotype is characterized by tubular aggre-
gate myopathy, congenital miosis, and hypocalcemia. These mutations
result in either prolonged Ca2+ entry following stimulation or the sponta-

neous entry of Ca2+ from the extracellular space to the cytoplasm. Interest-
ingly no hematopoietic abnormalities have been associated with this disease,
suggesting that the increased Ca2+ flux is either cell type-specific or not
severe enough to cause enhanced immune cell activation. Nonetheless,
the immunological features of these patients should be examined over time
to see if there is a late-onset immunological phenotype associated with
ORAI-1 activating mutations.
Homozygous deleterious variants in STIM1 give rise to an immunode-
ficiency with syndromic features including muscle hypotonia and defects in
tooth enamel, similar to that seen in ORAI-1 patients (OMIM 612783)
(Picard et al., 2009b; Wang et al., 2014). Clinical manifestations include
recurrent urinary tract infections, otitis media, pneumonia, bacterial sepsis,
and increased susceptibility to viral infection including chickenpox, CMV,
EBV, and disseminated Kaposi sarcoma indicating severe immune dysfunc-
tion. Unexpectedly, the patients also developed autoimmune manifestations
including thrombocytopenia, lymphadenopathy, and hepatosplenomegaly
(Byun et al., 2010). Patient cells were found to have defective extracellular
Ca2+ entry leading to poor activation of NK and T cells. Interestingly, patient
T cells showed an increase in terminally differentiated and exhausted cells,
suggesting a paradoxical altered stimulation or expansion in vivo due to a
lymphopenic state (Fuchs et al., 2012; Parry et al., 2016; Picard et al., 2009b).
In addition to the autosomal recessive disease caused by LOF mutations
in STIM1, an autosomal dominant disorder caused by GOF mutations in
STIM1 has been described with similar clinical presentation to ORAI1
autosomal dominant disease (OMIM 160565) (Morin et al., 2014; Nesin
et al., 2014; Noury et al., 2017). GOF mutations can lead to Stormorken
syndrome with miosis (OMIM 185070) thrombocytopenia, hyperactive
platelets, hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Causal
mutations include a missense mutation in STIM1 (R304W) that likely
affects the CC1 autoinhibitory domain, thus leading to a constitutively
active STIM1 molecule, as well as a D84E missense mutation in the
EF-hand, presumed to reduce baseline Ca2+ binding thus facilitating STIM1
aggregation. There was a corresponding increase in baseline cytoplasmic
Ca2+ levels in patient fibroblasts and enhanced STIM1 aggregation in
unstimulated cells. Although immunological phenotyping was not performed,
it would be interesting to see if T and NK cells show a hyperactive phenotype.
Why STIM1 hyperactive mutations lead to thrombocyte defects and bleeding
disorders while ORAI1 mutations do not remain an interesting question,
and may have to do with the dynamics of extracellular Ca2+ entry caused
by the causal variant.
3.2.10 EVER2
Like calcium, other divalent cations including zinc (Zn2+) and magnesium
(Mg2+) are also important for T cell-mediated signaling (see MAGT1 defi-
ciency) (Li et al., 2011; Yu et al., 2011). Primary epidermodysplasia ver-
ruciformis, characterized by eruptions of wart-like protrusions caused by
human papilloma virus (HPV) infection, is caused by biallelic LOF in
EVER1 or EVER2, ER resident proteins predicted to be transmembrane
channels (OMIM 226400) (Horton & Stokes, 2014). T cells from EV
patients show diminished responses to mitogenic stimuli, though the mech-
anism is incompletely understood (de Pereira, Carrasco, Neto, Rady, &
Tyring, 2003; Prawer et al., 1977). EVER1 and EVER2 interact with the
Zn2+ transporter ZnT-1 and modulate its function to block Zn2+-dependent
TF activity (Lazarczyk et al., 2008). Interestingly, the HPV16 E5 protein
inhibited this interaction and increased Zn2+-dependent transcription, sug-
gesting this pathway is targeted by HPV to mediate its own survival or rep-
lication. In T cells, EVER1 and EVER2 proteins are expressed at baseline but
are rapidly downregulated following activation, correlating with a rise in
intracellular Zn2+ concentration (Lazarczyk et al., 2012). Consistent with
this, B and T cells from EVER2-deficient patients had increased intracellular
Zn2+. Altogether, this suggests that EVER proteins function to inhibit
ZnT-1 and limit intracellular Zn2+ concentrations. Loss of protein expres-
sion, whether during T cell activation or in EVER-deficient patients, abro-
gates this inhibition causing Zn2+ accumulation. As Zn2+ modulates early
TCR signaling through inhibition of src homology region 2 domain-
containing phosphatase-1 (SHP1) recruitment to the TCR, prolonged/ele-
vated Zn2+ concentrations at baseline may alter signaling or induce T cell
anergy. Further work is needed to determine the role of EVER proteins
in regulating Zn2+-dependent T cell activation and how elevated Zn2+ con-
centrations effect T cell function over the prolonged periods, though it is
tempting to speculate that altered Zn2+ homeostasis accounts for the
T cell proliferative deficiencies in EVER2-deficient patients.
3.2.11 SH2D1A
An excellent example of how PIDs can guide investigators to discover
new genes and signaling pathways is hemizygous LOF variants in the gene
SH2D1A and its product signaling lymphocytic activation molecule
(SLAM)-associated protein (SAP). These variants were identified as the

genetic cause of X-linked lymphoproliferative disease (XLP) (OMIM
308240). XLP is defined by uncontrolled EBV infection including fatal
mononucleosis, vigorous polyclonal expansion of T and B cells, acquired
hypogammaglobulinemia, reduced NK cell functionality, and malignant
lymphoma (Coffey et al., 1998; Sayos et al., 1998). SAP binds phosphory-
lated tyrosine residues on the cytoplasmic tail of SLAM family members and
recruits the tyrosine kinases Lck and Fyn to initiate downstream signaling. In
addition, SAP binding blocks recruitment of the SHP1 and SHP2 phospha-
tases to SLAM receptors. SAP deficiency in XLP patients converts SLAM
family members from stimulatory to inhibitory receptors through decreased
Lck recruitment and increased phosphatase recruitment (Cannons, Tangye,
& Schwartzberg, 2011; Katz, Krummey, Larsen, Stinson, & Snow, 2014;
Latour et al., 2003; Nichols, Ma, Cannons, Schwartzberg, & Tangye,
2005). Interestingly, uncontrolled EBV infection in XLP is likely a bypro-
duct of the B cell tropism exhibited by EBV, as SLAM receptor signaling is
essential for CD8+ T cell-mediated killing of target B cells, but not of other
cell types (Palendira et al., 2011). In addition to the inability of XLP CD8+
T cells to control EBV-infected B cells, RICD is defective in patient T cells,
possibly accounting for a portion of the uncontrolled T cell response char-
acteristic of XLP as reactivated cells do not undergo apoptosis in response
to antigen, which is a normal control mechanism limiting the immune
response (Snow et al., 2009). This was due to increased recruitment of
SHP1 to the SLAM family receptor CD352 and SHP1-dependent down-
modulation of TCR-mediated signaling. Interestingly, silencing of CD352
also reduced RICD, suggesting it normally initiates an activating signal
that can contribute to TCR-mediated cellular activation, likely through
Lck recruitment and activation (Katz et al., 2014). Pharmacological inhi-
bition of SHP1/SHP2 or diacylglycerol kinase alpha (DGKα), which is also
upregulated in T cells from XLP patients, may yield a targeted way of
reversing the signaling abnormalities associated with SAP deficiency
(Ruffo et al., 2016).
3.2.12 PKCdelta
Biallelic LOF variants in PRKCD, the gene encoding protein kinase C delta
(PKCδ), cause an autosomal recessive disorder characterized primarily by
B cell hyperactivation, with mild defects in T cell activation (OMIM
615559) (Belot et al., 2013; Kuehn et al., 2013; Salzer et al., 2013a). Patients
suffer from recurrent infections, lupus-like autoimmunity with autoantibody
production, chronic lymphadenopathy, and splenomegaly derived mainly

from a hyperactivation/proliferation of patient B cells in the absence
of PKCδ.
3.3 Defects in Costimulatory Pathways

While the main T cell activating signal is unquestionably delivered through
the TCR, stimulation of other molecules, called costimulatory molecules,
are absolutely required for full T cell activation, effector function, memory
formation, and the prevention of T cell anergy (Chen & Flies, 2013). These
costimulatory molecules, of which CD28 is the best recognized, are cell sur-
face receptors that recognize ligands that are upregulated on APCs or target
cells upon infection. This costimulatory signal can involve signaling inter-
mediates that are either shared with the TCR or unique to costimulation.
In addition to the ability to receive costimulatory signals, T cells can also
deliver costimulatory signals during an immune response. In this section,
we will discuss PIDs associated with costimulatory signals provided to
and by T cells (Fig. 1).
3.3.1 CARMIL2/RLTPR Deficiency

Capping protein regulator and myosin 1 linker 2 (CARMIL2/RLTPR)
(OMIM 610859) is best known as a negative-regulator of actin capping pro-
tein (CP), which binds to the barbed end of actin filaments and prevents
monomer addition and is highly expressed in the immune system (Lanier,
Kim, & Cooper, 2015; Liang, Niederstrasser, Edwards, Jackson, &
Cooper, 2009). The essential role of CARMIL2 in CD28-mediated signal-
ing and nTreg formation was originally identified in a rescue screen for mice
expressing LAT (Y136F) (Liang et al., 2013). CARMIL2 translocates to
CD28/CD80 microclusters at the IS and is essential for the recruitment
of PKC-θ and CARD-containing MAGUK protein 1 (CARD11). Interest-
ingly, the mutant form of CARMIL2 identified in this rescue screen was
stable, recruited to CD28/80 complexes, and could still bind CP, suggesting
additional roles of CARMIL2 other than the regulation of actin filaments.
These points were later clarified as CARMIL2 was found to act as a scaffold-
ing protein within the CD28 pathway, bridging CD28 to CARD11, thus
inducing CARD11-mediated NF-κB activation (Roncagalli et al., 2016).
Biallelic mutations in CARMIL2 have recently been identified as a cause
of an autosomal recessive autoimmune disease (Schober et al., 2017;
Sorte et al., 2016; Wang et al., 2016). In one study, the patients suffered from
mucocutaneous candidiasis, multifocal tuberculosis, recurrent bacterial lung
infections, subcutaneous Staphylococcus, asthma associated with severe aller-

gic skin lesions comprising psoriasiform hyperplastic epidermis and spongio-
sis, with superficial perivascular CD8+ T cell infiltrates and EBV viremia in
some patients (Wang et al., 2016). A second report described patients with a
similar phenotype comprising failure to thrive, chronic diarrhea, recurrent
skin (staphylococcus, skin warts, and eczema), and upper respiratory infec-
tions (Schober et al., 2017). Interestingly, this report identified disseminated
EBV+ smooth muscle tumors in all patients, presenting variably in the gut,
liver, brain, spleen, and kidney explaining the susceptibility to EBV as seen
in the first study. All patients had biallelic mutations leading to the loss or
reduction of CARMIL2/RLTPR protein with a recessive MOI. Immuno-
phenotyping of patients revealed reduced Treg numbers and an increased
percentage of naı̈ve CD4+ and CD8+ T cells coupled with reduced memory
populations. There was an apparent defect in CD28-mediated T cell costi-
mulation. While stimulation through CD3 alone or with PMA/I proceeds
normally, patient T cells did not upregulate CD25 or CD69, make TNF,
induce p65 (RELA) phosphorylation or undergo proliferative expansion
when CD28 activating antibodies were added to CD3 stimulation. Patients
also displayed B and NK cell-intrinsic defects, though the addition of IL2 to
the culture medium rescued both NKG2D expression and degranulation in
NK cells and CD8+ T cells, possibly by compensating for defects in CD28-
mediated costimulation. While no defects in cellular migration or synapse
formation were described in either CARMIL2-deficient mice or humans,
it may be interesting to determine if CARMIL2 is also involved in these
actin-dependent processes, given the role of CAMRIL2 in the migration
of other cell types.
3.3.2 CTLA4
Immune homeostasis is a balance between the ability to receive
costimulatory signals and dampen the immune response by inhibiting
CD28-dependent signaling as a form of checkpoint regulation. This is largely
accomplished through the immune checkpoint protein CTLA4 expressed
on Tregs and activated T cells. CTLA4 binds CD80 and CD86 with high
affinity, effectively competing with CD28 ligand binding. CTLA4 binding
removes CD80 and CD86 from the cell surface by transendocytosis to
dampen the T cell immune response (Sansom, 2015; Tivol et al., 1995;
Walker & Sansom, 2011; Waterhouse et al., 1995). Coding variants in
CTLA4 have long been identified as potential risk alleles in common auto-
immune disorders such as Graves’ disease, Celiac disease, T1DM, and
systemic lupus erythematosus (Barreto et al., 2004; Nistico et al., 1996; Ueda
et al., 2003). More recently, an autosomal dominant disease, termed
“CTLA-4 haploinsufficiency with autoimmunity and infiltration” (CHAI)
disease has been described due to heterozygous LOF variants in CTLA4
(OMIM 616100) (Kuehn et al., 2014; Schubert et al., 2014). Like
CTLA4-deficient mice, patients develop a T cell lymphocytic infiltrative
disease in several tissues including intestines, lungs, bone marrow, central
nervous system, and kidneys with lymphadenopathy and splenomegaly asso-
ciated with reduced CTLA4 expression levels. On a cellular level, patient
Tregs express less FOXP3 and CD25 and are less inhibitory than control
Tregs while conventional T cells are hyperproliferative in response to anti-
genic stimulation. Importantly, this disease can be treated with CTLA4-Ig,
which replaces, pharmaceutically, the natural function of CTLA-4 in
patients (Lee et al., 2016). CTLA4 deficiency, like other forms of autoim-
mune lymphoproliferative disease (see below), is incompletely penetrant,
with only about 50% of mutation-bearing individuals showing clinically
appreciable disease despite reduced CTLA4 expression. Whether these clin-
ically asymptomatic individuals have protective variants in other genes or the
disease is precipitated by susceptibility genes or an immunological/environ-
mental event remains to be explored.
3.3.3 ICOS
Inducible T cell costimulatory (ICOS) is upregulated on the surface of acti-
vated T cells, particularly T follicular helper cells (Tfh), with structural and
sequence homology to CD28 and CTLA-4 (Hutloff et al., 1999). Ligation
of ICOS with an activating antibody provides a strong costimulatory signal
to responding T cells leading to enhanced proliferation, primarily through
PI3K recruitment to the YMFM motif in the cytoplasmic tail of ICOS
(Harada et al., 2003; Yong, Salzer, & Grimbacher, 2009). ICOS is par-
ticularly important for the development of T cell-dependent antibody
responses and the germinal center reaction through a combination of
ICOS-dependent Tfh formation, migration into the germinal center, and
costimulatory events necessary for the delivery of T cell help to GC B cells
(Dong, Temann, & Flavell, 2001; Wikenheiser & Stumhofer, 2016; Xu
et al., 2013; Yong et al., 2009). Biallelic LOF mutations in ICOS lead to
autosomal recessive combined variable immunodeficiency (CVID) with
recurrent bacterial infections, sinusitis, bronchiectasis, pneumonia, GI infec-
tions with diarrhea, hepatosplenomegaly, and in some cases malignancy cau-
sed by decreased class-switched and memory B cells, decreased serum
immunoglobulins, and attenuated germinal center formation (OMIM

607594) (Grimbacher et al., 2003; Salzer et al., 2004; Warnatz et al.,
2006). Although T cell populations were initially reported to be intact in
ICOS-deficient patients, it was later discovered that patient T cells did
not produce IL-10 or IL-17 upon stimulation with antibodies against
CD3/28 or CD3/ICOS. Additionally, patients have a significant reduction
in CXCR5+ Tfh cells, indicating an essential role of ICOS signaling in the
differentiation of these cells in vivo (Bossaller et al., 2006; Warnatz et al.,
2006). Thus, it seems likely that the B cell defects in ICOS patients arise
from a selective defect in the formation, migration, or function of Tfh cells.
3.3.4 CD40 Ligand (CD40LG/CD154)

Hemizygous LOF mutations in CD40LG, encoding the T cell-expressed
TNF-like ligand for CD40 (CD154), cause an X-linked hyper-IgM syn-
drome characterized by recurrent bacterial infections, ulcerative stomatitis,
gingivitis, due to low levels of class-switched antibodies, loss of germinal
center reactions, and low B cell isotype switching and memory formation
but no appreciable defect in T cell populations (OMIM 308230) (Allen
et al., 1993; DiSanto, Bonnefoy, Gauchat, Fischer, & de Saint Basile,
1993; Korthauer et al., 1993). Upon activation, T cells upregulate CD154
which is capable of binding the TNF receptor superfamily member CD40
(formerly known as TNFRSF5) on the surface of B cells and other APCs.
During T-dependent B cell responses in the germinal center reaction, liga-
tion of CD40 by CD154 at the IS induces multiple signaling pathways in the
responding B cells, including TRAF-dependent NF-κB signaling, PI3K
activation, JNK activation, and JAK/STAT signaling. These signaling events
enhance B cell adhesion, survival, proliferation, class switching, and affinity
maturation, while lack of CD40 engagement can lead to apoptosis of acti-
vated B cells (Elgueta et al., 2009). Thus, the presence of CD154 on
CD4+ Tfh cells is absolutely critical for their effector function.
3.3.5 CD27/CD70
Stimulation of CD27, a member of the TNF family of receptors expressed
on T, B, and NK cell populations, by its ligand CD70 (expressed on B cells
and APCs) results in the activation of NF-κB and c-Jun N-terminal kinase
(JNK) resulting in enhanced effector and memory differentiation (Denoeud
& Moser, 2011; Hendriks et al., 2000). Biallelic LOF mutations in CD27
cause an EBV-associated lymphoproliferative disorder with symptoms vary-
ing from an asymptomatic memory B cell deficiency to EBV-driven
hemophagocytosis, lymphoproliferation, hypogammaglobulinemia, and

malignancy (OMIM 615122) (Salzer et al., 2013b; van Montfrans et al.,
2012). Interestingly, while patient T cells had minor proliferative defects
to ligands that can engage CD27 in vitro, EBV-specific T cells were
detected in the memory compartment and showed normal effector func-
tion, so the reason for uncontrolled EBV-driven lymphoproliferation was
not understood. This was clarified in two recent publications identifying
and characterizing patients with a similar disease of immunodeficiency
and EBV-driven malignancy in patients with biallelic LOF mutations in
the CD27 ligand, CD70 (Abolhassani et al., 2017; Izawa et al., 2017).
The authors show that EBV-specific T cells do not expand well when
stimulated with EBV-infected B cells and CD8+ T cells had reduced cyto-
lytic capacity against CD70-deficient target cells, likely due to reduced
NKG2D and 2B4 expression. Importantly, this was phenocopied when
CD27/CD70 interactions were blocked with inhibitory CD27 antibodies.
It is likely that similar defects in EBV-specific T cell activation, prolifera-
tion, or effector function were simply unappreciated in CD27-deficient
patients, possibly due to use of strong agonists to stimulate T cell responses.
3.4 Defects of Cytokine Signaling

Cytokines are key mediators of the innate and adaptive immune response.
Chief among their T lymphocyte duties are T cell selection, maturation, sur-
vival, proliferation, effector function, and effector/memory differentiation.
Several PIDs are due to cell-intrinsic defects in cytokine signaling. In the
following section, we will discuss PIDs of cytokines, cytokine receptors,
and their downstream Janus kinase (JAK) and signal transducer and activator
of transcription (STAT) signaling mediators. Several additional PIDs are
caused by variants in T cell-secreted cytokine signaling. However, we will
not discuss these PIDs in detail because T cell cytokine production defects
primarily affect other cell types leaving T cell function otherwise intact. Of
the PIDs not described in detail below, several are notable including alter-
ations in interferon gamma (IFNγ) pathway causing recurrent mycobacterial
infections, the interleukin (IL)-10 pathway, associated with early onset IBD,
and the IL-17 pathway (IL-17F and ACT1) which result in familial
candidiasis.
3.4.1 CD132/Common Gamma Chain

LOF mutations in the common gamma chain (CD132) result in an X-linked
SCID with frequent bacterial, viral, and fungal infections with defects in
antibody responses, athymia, reduced NK cell numbers, and absent

T lymphocytes (OMIM 300400) (Noguchi et al., 1993). CD132 is a cyto-
kine receptor chain shared among multiple cytokine receptors including the
those for IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, and thymic stromal lympho-
poietin (Rochman, Spolski, & Leonard, 2009). Several of these cytokines are
critical for T cell development and survival, thus explaining the T cell SCID
phenotype. As discussed below, defects in individual cytokine receptor
chains that pair with CD132 cause more specific defects in T cell develop-
ment or effector function.
3.4.2 IL7Rα
Biallelic LOF mutations in IL-7R alpha subunit result in an autosomal reces-
sive T/B+/NK+ SCID phenotype with absent peripheral T cells, opportu-
nistic infections, splenomegaly and lymphadenopathy, candida, pneumonia,
and diarrhea (OMIM 608971) (Puel, Ziegler, Buckley, & Leonard, 1998).
This defect likely occurs during thymic development during which IL-7 is
critical for survival and proliferation, though IL-7 is also essential for mature
T cell survival and homeostasis in the periphery (Giliani et al., 2005).
3.4.3 CD25
Biallelic LOF mutations in the alpha subunit of IL2RA (CD25), which com-
bines with IL2RB and CD132 to form a high-affinity IL-2 receptor, cause an
autosomal recessive immunodeficiency with autoimmunity (OMIM
606367) (Caudy, Reddy, Chatila, Atkinson, & Verbsky, 2007; Goudy
et al., 2013; Sharfe, Dadi, Shahar, & Roifman, 1997). Patients develop recur-
rent viral, bacterial, and fungal infections but also large-scale autoimmune
disease including lung inflammation and infiltration, hepatosplenomegaly,
enteropathy, eczema and dermatitis, and T1DM. Interestingly, these clinical
features combine IPEX-like disease with a T cell-specific immunodefi-
ciency. CD25 deficiency results in decreased RICD as well as reduced Treg
function because IL-2 is required for both Treg survival and effector function
(Barron et al., 2010; Pandiyan, Zheng, Ishihara, Reed, & Lenardo, 2007).
Additionally, patient T cells fail to make the immunosuppressive cytokine
IL-10 following TCR stimulation which may contribute to enterocolitis.
Loss of T cell homeostasis, Treg function, and IL-10 production may
account for the nonspecific T cell activation and expansion and IPEX-like
autoimmunity associated with CD25 deficiency. CD25 is also required for
TCR-induced proliferation, the absence of which leads to defective
antigen-specific responses and the recurrent infections associated with
CD25 deficiency. Thus CD25 is critical for IL-2 regulation of both effector
and regulatory T cell function and overall control of the peripheral lymphoid
compartment (Willerford et al., 1995).
3.4.4 IL21/IL21R
Biallelic LOF mutations in the IL-21 (OMIM 615767) and the IL-21 recep-
tor (IL-21R) (OMIM 615207) cause a similar recessive immunodeficiency
characterized by recurrent respiratory tract infections, hepatitis, liver fibrosis,
recurrent diarrhea, septicemia, impaired B cell class switching, and impaired
T cell responses to candida antigens (Kotlarz et al., 2013; Salzer et al., 2014).
IL-21 signaling enhances T helper (Th)17 and Tfh differentiation while
inhibiting Treg differentiation, which could account for the T cell abnor-
malities, and is possibly related to the development of colitis (Leonard &
Wan, 2016; Tian & Zajac, 2016). IL-21 also enhances B cell class switching,
which leads to a B cell autonomous defect in humoral immunity in these
patients.
3.4.5 IL12RB1/IL-12B
IL-12 signaling is essential for the differentiation of naı̈ve T cells into Th1
cells. Biallelic LOF mutations in the beta subunit of the IL-12 receptor
(IL-12RB1) (OMIM 614891) or the p40 subunit of IL-12 (IL-12B)
(OMIM 614890) result in a clinically limited PID with a selective suscep-
tibility to mycobacteria, candida, and salmonella infections (Altare et al.,
1998a, 1998b; de Jong et al., 1998; Picard et al., 2002). Patients with
IL-12B deficiency do not produce IL-12 or the Th1 cytokine IFNγ which
is necessary for the control of intracellular bacterial infections. IL-12RB-
deficienct patients have reduced Th1 responses and IFNγ production upon
stimulation. IL-21RB1 and IL-12B-deficient patients also had defects in
IL-17 producing Th17 cell formation, thus accounting for the recurrent
fungal infections (de Beaucoudrey et al., 2008). Importantly, the nature
of the mutation in this pathway is critical for treatment, because only
IL-12 deficient, and obviously not IL-12RB1 deficient, patients can be trea-
ted by the administration of exogenous IL-12.
3.4.6 TYK2
An autosomal recessive immunodeficiency with recurrent respiratory, viral,
mycobacterial, and intracellular bacterial infections is caused by LOF muta-
tions in tyrosine kinase 2 (TYK2), the JAK family member kinase associated
with signaling downstream of IFNα, IL-12, IL-10, and IL-23, among others
(OMIM 611521) (Kreins et al., 2015; Minegishi et al., 2006; Watford &
O’Shea, 2006). As with mutations in other JAK/STAT proteins, the com-
plex and varied patient phenotypes likely result from defects in signaling
from multiple cytokine receptors that rely on TYK2. Thus, the viral and
bacterial susceptibility of TYK2-deficient patients seem attributable to the
loss of IFNα and IL-12 signaling, respectively. Indeed Tyk2-deficient cells
have reduced IFNα, IL-10, and IL-12 receptor expression and diminished
IFNα, IL-10, IL-23, and IL-12 signaling. Importantly, patients have dimin-
ished IL-12-dependent IFNγ production, but this was not as severe as in
IL12R-deficient patients. Perhaps there is a degree of compensation by
other JAK family members. Together, this indicates that TYK2 deficiency
is indeed an amalgamation of incomplete signaling defects downstream of
multiple cytokine receptors.
3.4.7 JAK1
JAK1 pairs with JAK3 to mediate signaling downstream of the common-
gamma chain cytokine receptors (OMIM 147795) (Lin & Leonard,
2017). Three patients with JAK1 mutations from a single kindred presented
with atopic dermatitis, allergies, hepatosplenomegaly, autoimmune thyroid
disease, and failure to thrive caused by an autosomal dominant JAK1 muta-
tion (Del Bel et al., 2017). The causal A634D missense mutation lies within
the JAK1 inhibitory domain and enhances phosphorylation of STAT3 in
T cells following IL-6 stimulation. Patients treated with ruxolitinib, a
JAK1/2 inhibitor, showed marked clinical improvement after a month of
treatment, again emphasizing the importance of understanding the molec-
ular cause of disease in designing an individualized medical intervention (Del
Bel et al., 2017).
3.4.8 JAK3
Biallelic LOF mutations in JAK3 cause an autosomal recessive SCID
with recurrent upper respiratory tract infections, diarrhea, meningitis, absent
peripheral lymph nodes, reduced T and NK cell numbers, reduced TCR-
dependent T cell activation, and B cell activation deficiencies with hyp-
ogammaglobulinemia (OMIM 600802) (Macchi et al., 1995; Russell et al.,
1995). As JAK3 is the sole JAK responsible for signaling through CD132,
JAK3 deficiency largely phenocopied CD132 X-linked SCID (Lin &
Leonard, 2017). In patient T cells, JAK3 deficiency results in abrogation of
STAT protein phosphorylation after stimulation with all tested gamma chain
cytokines, thus confirming the interrelated nature of these two PIDs.
3.4.9 STAT3
Deleterious variants in STAT3 have been linked to several separate PIDs.
The first is caused by dominant negative (DN) mutations in STAT3
resulting in an autosomal dominant hyper-IgE syndrome (Job (pronounced
with a long “o”) syndrome, OMIM 147060). Clinical features of Job syn-
drome include eczema, skin abscesses, Staphylococcus infection, recurrent
fungal infections, increased IgE, and eosinophilia (Holland et al., 2007;
Minegishi et al., 2007). Three concurrent reports demonstrated that DN
STAT3 mutations specifically impaired the development and function of
Th17 cells (de Beaucoudrey et al., 2008; Ma et al., 2008; Milner et al.,
2008). Naı̈ve T cells from Job syndrome patients were also defective in pro-
liferation and differentiation into central memory T cells which leads to poor
suppression of latently infected EBV and Zoster viruses (Siegel et al., 2011).
The second PID caused by STAT3 variants is an autosomal dominant disease
caused by activating STAT3 mutations which causes an infantile onset mul-
tisystem autoimmune disease (OMIM 615952) (Flanagan et al., 2014;
Milner et al., 2015). Patients variably suffer from interstitial pneumonitis,
autoimmune enteropathy, arthritis, eczema, T1DM, hypothyroidism, auto-
immune cytopenias, hepatosplenomegaly, lymphadenopathy, and large
granular lymphocytic T cell leukemia. Tregs from patients are reduced in
number and functional markers, suggesting that decreased Treg function
may contribute to the autoimmune disease. Interestingly, while STAT3
activity was increased, stimulation-dependent phosphorylation of STAT1
and STAT5 were diminished. The STAT1 and STAT5 defects are likely
due to tachyphylaxis mediated by STAT3-driven expression of suppressor
of cytokine signaling 3, thus dampening the activation of other STATs.
Interestingly, pharmacological blockade of IL-6, which signals though
STAT3, resulted in dramatic clinical improvement. Thus, the patient phe-
notype is due to an increase in STAT3 signaling and a decrease in sensitivity
to other cytokines. A decrease in STAT5 activation downstream of IL-2
could explain the overlap in Treg phenotypes, which depend on IL-2 sig-
naling, in patients with STAT5b deficiency and activating STAT3 variants
(see below). Given the activating nature of the STAT3 variants in this dis-
ease, and the success of IL-6 blockade, ruxolitinib likely represents a ther-
apeutic option for these patients.
3.4.10 STAT5b
Homozygous LOF mutations in STAT5b (activated downstream of IL-2,
IL-4, and various growth hormones) are associated with an autosomal
recessive disorder of growth hormone insensitivity, T cell lymphopenia, and

Treg deficiency (OMIM 245590) (Cohen et al., 2006; Kofoed et al., 2003).
Patient T cells do not upregulate CD25 upon stimulation to the same degree
as control cells and express low levels of FOXP3 protein in freshly isolated
CD25high cells, indicating loss of natural (n)Treg populations. Indeed, these
Stat5b-deficient CD4+/CD25high nTregs are poorly suppressive in in vitro
tests of Treg functionality. Interestingly, despite the lymphopenia and reduced
nTreg activity, overt immunodeficiency or autoimmunity is so far not associ-
ated with STAT5b deficiency. It may be that STAT5a can largely compensate
for STAT5b deficiency, as it does in mice (Moriggl et al., 1999). Interestingly,
a recent study has identified a patient with an autoimmune lymphoprolifera-
tive syndrome (ALPS)-like disease but no growth hormone abnormality
associated with a DN STAT5b variant (Majri et al., 2018).
3.5 Defects in Adhesion, Migration, or Cytoskeletal

Organization
The immune system is unique in that it is not a static organ and must be able
to respond to infection throughout the body. As such, cells of the immune
system are highly motile and interact with multiple cell types to both migrate
to their intended destination, receive activation signals, and exert effector
function. These processes depend on coordinated function of the actin cyto-
skeleton and integrin cell adhesion molecules that are regulated downstream
of both antigen receptors and GPCRs. These receptors coordinate actin
responses through the activation of GTPase guanine nucleotide exchange
factors (GEFs) and GTPase-activating proteins that coordinate Rac1,
CDC42, and RhoA GTP loading and thus activation of both actin nucleat-
ing complexes, such as the ARP2/3 complex, downstream of both CDC42
and Rac1, and myosin-mediated contractility, mediated by RhoA. In addi-
tion, other proteins, such as actin capping and uncapping proteins, are also
regulated following receptor stimulation. These all lead to a highly dynamic
actin network that is critical for T cell effector function (Comrie &
Burkhardt, 2016). Here, we will review PIDs associated with defects in
cytoskeletal regulators, chemokine signaling, and integrin-mediated cell
adhesion (Fig. 1) (Moulding, Record, Malinova, & Thrasher, 2013).
3.5.1 RASGRP1
Homozygous LOF mutations in RAS guanyl releasing protein 1
(RASGRP1) cause recurrent bacterial and viral infections with low CD4+
T cells, B cells, and NK cells, and an inverted CD4+/CD8+ ratio with
primarily effector or memory CD8+ T cells (Mao et al., 2017; Salzer et al.,
2016). RASGRP1 is a Ras GEF with a DAG-binding domain that is
highly expressed in hematopoietic lineages (OMIM 603962). Studies in
knockout mice show reduced peripheral T cell populations due to defec-
tive Ras and extracellular signal-regulated kinase (ERK) activation leading
to diminished proliferation and impaired thymocyte development (Dower
et al., 2000). Conversely, overexpression of RASGRP1 enhanced ERK
and Rac activation in Jurkat T cells, further solidifying the importance
of RASGRP1 in this pathway (Ebinu et al., 2000). Fitting with this,
CD4+ and CD8+ T cells from RASGRP1 patients had intact calcium flux
responses but diminished ERK activation, CD69 upregulation, and pro-
liferation upon TCR-induced activation (Mao et al., 2017; Salzer et al.,
2016). Additionally, patient T cells had defective actin polymerization
and reduced retrograde flow in migrating lymphocytes, which was asso-
ciated with defects in RhoA activation and was reversible by lenalidomide
treatment, which targets this pathway.
3.5.2 DOCK2
Dobbs et al. identified biallelic LOF mutations in dedicator of cytokinesis 2
(DOCK2), which encodes a hematopoietic-specific RAC1 GEF, as a cause
of early onset and severe viral and bacterial infections (OMIM 616433)
(Dobbs et al., 2015; Fukui et al., 2001). Rac1-GTP loading, chemotaxis,
and actin polymerization downstream of chemokine receptor activation
were defective in patient T cells. Perhaps more interestingly, patient NK cells
had defective mitogen activation protein kinase kinase (MEK) and ERK sig-
naling. These results are intriguing as DOCK2 and Rac1 are not known to
directly affect the MEK/ERK pathway, which may suggest that DOCK2
acts as a GEF for Ras, like RASGRP1 (see above). Additionally, patient
NK cells did not produce IFNγ after cytokine stimulation while patient
fibroblasts did not produce interferon alpha (IFNα) following viral infection.
These results may reflect altered intracellular trafficking of cytokine receptors
and interferon molecules, since DOCK2 plays an essential role in molecular
trafficking through regulation of microtubule dynamics (Tanaka et al.,
2007). As DOCK2 activity is regulated by its association with ELMO1,
and cannot assert its GEF activity in the absence of the Rac1/ELMO1/
DOCK2 trimeric complex, it is possible that a similar PID could arise
through LOF mutations in ELMO1 (Brugnera et al., 2002; Sanui et al.,
2003; Stevenson et al., 2014).
3.5.3 DOCK8
Biallelic LOF mutations in another DOCK-180-related protein (DOCK8)
cause a PID characterized by recurrent sinopulmonary and cutaneous bac-
terial and viral infections, and elevated IgE levels with severe atopy and ana-
phylaxis termed DOCK8 immunodeficiency syndrome (OMIM 243700)
(Zhang et al., 2009). Patients have extremely low T and NK cell counts with
poor ex vivo CD8+ T cell proliferation. This progressive loss of T and NK
cells is due to both the aforementioned proliferative defects, and a failure in
DOCK8-deficient T and NK cellular integrity when confined in a 3D envi-
ronment, such as dermal tissue or an artificial collagen matrix, leading to cell
elongation, nuclear deformation, and a form of cell death called cytothripsis
(Zhang et al., 2014a). Interestingly, while DOCK8 and CDC42 knock-
down resulted in a similar phenotype, knockdown of Wisckott–Aldrich
syndrome protein (WASP), the main regulator of ARP2/3 downstream
of CDC42, did not. This suggests that maintenance of cellular integrity in
confined spaces is an actin-independent function of DOCK8/CDC42.
Indeed, knockdown of PAK1/2, another downstream effector of CDC42,
caused enhanced cytothripsis. Cellular elongation of DOCK8-deficient cells
is accompanied by a deformation of the nucleus, suggesting that the target of
PAK1/2 was critical for maintaining nuclear rigidity under mechanical stress.
It is possible that PAK1/2, and by extension DOCK8, is regulating interme-
diate filaments such as lamins and vimentins to maintain nuclear integrity/
rigidity. The lack of a chemotactic defect in DOCK8 T cells may also indicate
that there is another GEF capable of regulating CDC42 and WASP activation
as these are hallmarks of Wiskott–Aldrich syndrome (WAS), see below.
DOCK8 may also regulate a specific subset of CDC42 effectors by acting
as both a GEF and a molecular scaffold that bridges CDC42 to downstream
effectors. DOCK8 and DOCK2 deficiencies also serve to highlight the great
variety of immunodeficiencies that can arise from alterations to cytoskeletal
dynamics, as defects in either a RAC or CDC42 GEF can cause such varied
cellular and clinical phenotypes.
3.5.4 Coronin 1A
One aspect of the actin cytoskeleton in lymphocytes is its highly dynamic
nature, both during migration and IS formation. In order to maintain this
highly dynamic structure actin polymerization must be accompanied by
turnover of old F-actin filaments and generation of G-actin monomers.
The coronin family of proteins plays a role in both functions by promoting
or substituting for ARP2/3 to initiate a highly flexible branched actin
network while simultaneously protecting actin filaments from cofilin at the

barbed end and enhancing cofilin activity and actin disassembly at the
pointed end (Chan, Creed, & Bear, 2011). Coronin 1A is highly expressed
in the immune system, and mice deficient in coronin 1A shows a selective
loss of peripheral T cell numbers with defects in cellular polarization and
migration in response to chemokine, but not TCR, stimulation (Foger,
Rangell, Danilenko, & Chan, 2006). Interestingly, coronin 1A-deficient
naı̈ve T cells, but not effector or memory cells, underwent spontaneous
caspase-mediated apoptosis. This increased cell death was due to high levels
of polymerized actin at baseline in naı̈ve T cells and could be reversed by
actin-depolymerizing agents. Shiow et al. identified a coronin 1A E26K
variant that causes coronin 1A mislocalization and peripheral T cell defi-
ciency in mice (Shiow et al., 2008). The authors concurrently identified
the first case of human coronin 1A deficiency resulting in a T/B+/
NK+ SCID phenotype with varicella infection (OMIM 615401). Identifi-
cation of more patients, each with biallelic LOF mutations in coronin
1A indicated minor involvement of B and NK cells in some patients,
and expanded the clinical phenotype to include EBV-associated B cell lym-
phoproliferation, HPV infection, extensive cutaneous warts, molluscum
contagiosum, oral-cutaneous herpetic ulcers, disfiguring granulomatous
tuberculoid leprosy, recurrent URT infections, and bronchiectasis
(Moshous et al., 2013; Stray-Pedersen et al., 2014a; Yee et al., 2016). Like
T cells from mouse models, patient T cells had increased baseline F-actin,
decreased thymic output, and increased peripheral apoptosis. Interestingly,
coronin 1A is known to play a role in TLR-2 signaling during Mycobacte-
rium leprae infection, possible contributing to the patient phenotype in a
T cell-independent manner (Tanigawa et al., 2009). While the role of cor-
onin 1A in actin turnover, thymic output, and cell survival is consistently
observed, there is a conflicting data concerning the importance of coronin
1A in TCR singling. Specifically, T cells from coronin 1A KO mice have a
defect in TCR-mediated calcium flux this was not observed in patient’s
cells and, moreover, patient cells are able to kill target cells efficiently
(Shiow et al., 2008; Yee et al., 2016). How exactly increased F-actin accu-
mulation may be linked to spontaneous apoptosis in coronin-1A-deficient
T cells necessitates further study, as targeting this pathway may prove to be
therapeutically beneficial to these patients. Interestingly, F-actin polymer-
ization in coronin 1A KO cells causes high baseline JNK phosphorylation,
suggesting a possible role of JNK in caspase-mediated apoptosis of these
cells (Mugnier et al., 2008).
3.5.5 WASP
WASP is a hematopoietic-specific activator of the ARP2/3 complex which
signals downstream of CDC42 (Thrasher, 2002). It is a good example of a pre-
viously unknown protein that was identified and functionally characterized
through the study of PIDs. WASP was originally identified as the affected pro-
tein in WAS through a positional cloning strategy (Derry, Ochs, & Francke,
1994). Mutations in the WAS gene lead to three different X-linked recessive
disorders: WAS, severe congenital neutropenia, and X-linked thrombocyto-
penia. We will discuss WAS in more detail. Depending on the causal variant,
WAS can be associated with eczema, thrombocytopenia, recurrent infections,
bloody diarrhea, autoimmunity, and hematopoietic malignancy. This disease
usually follows a fatal course without HCST due to defects in multiple hema-
topoietic lineages including T, B, and NK cells (OMIM 301000). WASP is
critical for T cell development, as well as multiple actin-mediated cellular
functions, including microvilli formation (important for slow rolling and
adhesion on endothelium), migration, actin polymerization, protein recruit-
ment to the IS, and TCR-mediated cellular activation/proliferation (Bouma,
Burns, & Thrasher, 2009; Thrasher & Burns, 2010). Of note, WASP is
activated downstream of CDC42, for which DOCK8 is a critical GEF and
activator. While the patients share some clinical overlap, DOCK8 cells are
capable of normal chemotaxis suggesting intact cytoskeletal responses in these
cells, either compensated by another CDC42 GEF or by RAC1-mediated
activation of the WASP homologue, WAVE2. WASP-deficient T cells are
not known to exhibit the stretched T cell morphology in 3D environments
characteristic of DOCK8 T cells which supports the idea that DOCK8 defi-
ciency involves nonactin-dependent pathogenic mechanisms.
3.5.6 WIP
WIP (WASP-interacting protein) was originally identified in a yeast two-
hybrid screen for WASP-binding partners and induces actin polymerization
in lymphoid cells when overexpressed (Ramesh, Anton, Hartwig, & Geha,
1997). WIP both regulates the localization of WASP and protects it from
calpain-mediated cleavage and degradation (Chou et al., 2006). WIP, like
WASP, regulates actin dynamics during T cell activation and is essential
for both CD3/28-mediated CD25 upregulation and proliferation (Anton
et al., 2002; Volkman, Prehoda, Scott, Peterson, & Lim, 2002). Given that
a large percentage of WAS mutations occur within the WIP-interacting
domain of WASP, it is perhaps unsurprising that homozygous WIP LOF
variants cause a WAS-like immunodeficiency characterized by eczema,
papulovascular lesions on the scalp, ulcerative lesions on the hard palate and
tongue, thrombocytopenia, and respiratory distress (OMIM 614493) (Lanzi
et al., 2012). WIP-deficient patients have reduced CD8+ T cell numbers and
defective T and NK cell function. Importantly, both WIP and WASP pro-
teins were undetectable in patient cells, and exogenous expression of WIP
was able to rescue WASP expression—showing that they are obligate part-
ners in a stable protein complex. WIP deficiency is thus an excellent example
of how mutations in different proteins in the same pathway can present with
identical clinical phenotypes.
3.5.7 Moesin
Hemizygous mutations in the X-linked gene encoding the Ezrin/Radixin/
Moesin (ERM) family member moesin were identified in seven affected
males from five kindreds suffering from profound T, B, and NK cell
lymphopenia, hypogammaglobulinemia, monocytopenia, neutropenia, poor
vaccine responses, bacterial infections, and zoster virus infections (OMIM
300988) (Delmonte et al., 2017; Lagresle-Peyrou et al., 2016). These variants
lead to either unstable protein or truncated protein products in affected indi-
viduals. Moesin is involved in linking plasma membrane proteins to the
underlying actin cytoskeleton through its FERM and actin-binding domain,
respectively (Fehon, McClatchey, & Bretscher, 2010). This can control the
mobility, localization, and function of key immunological regulators, such as
the intercellular cell adhesion molecule (ICAM1) (Comrie, Li, Boyle, &
Burkhardt, 2015). In addition, moesin regulates cortical actin networks
and polarization of human T cells in response to CXCL12 (Brown et al.,
2003). Moesin-deficient patient T cells are defective in antigen-induced pro-
liferation. While conjugate formation and actin polymerization at the IS were
generally intact, the authors did not look at the dynamic redistribution of
ERM-binding partners during IS formation leaving open the possibility of
more subtle defects in IS formation. Additionally, patient T cells had defec-
tive chemotaxis and enhanced integrin-mediated adhesion due to increased
integrin expression and affinity maturation, though exactly how moesin reg-
ulates these integrin changes have not been worked out. Accompanying the
patient lymphopenia was a relative loss of naı̈ve T cells and an expansion of
senescent T cells, possibly due to lymphopenia-induced expansion. It should
be noted that senescent cells activate poorly, so whether the poor expansion
of T cells from PBMCs represents a true signaling defect or a byproduct of
increased T cell senescence is not currently known. The identification of
moesin-deficient patients demonstrates the sometimes discordant phenotypes
between mouse and man, as studies in moesin knockout mice have shown
relatively mild immunological defects, likely due to redundant function of
the related ezrin protein (Hirata et al., 2012). Nevertheless, moesin deficiency
resulted in reduced thymic and bone marrow egress of T and B cells causing
lymphopenia in mice. In humans, who may rely more on moesin, defects in
migration from lymphoid organs may be compounded which could explain
the severe lymphopenic status if hematopoietic progenitors cannot migrate to
or from the thymus efficiently.
3.5.8 CXCR4
Activating mutations in the chemokine receptor CXCR4 cause an auto-
somal dominant disorder called WHIM syndrome (WHIMS) characterized
by peripheral neutropenia due to retention in bone marrow, chronic HPV
infection with skin warts, upper respiratory tract infections, and hyp-
ogammaglobulinemia (OMIM 193670). Patient mutations reduce CXCR4
internalization following ligand engagement, thus leading to enhanced stim-
ulation by and migration toward CXCL12 (Balabanian et al., 2005;
Hernandez et al., 2003; Lagane et al., 2008). As mentioned before, T cells
are highly migratory and must also form a stable IS to become activated
and exert effector functions. Thus, T cells must balance the two discordant
functions of chemokine-driven “go” signals and TCR-mediated “stop” sig-
nals to function properly. While T cells from normal donors preferentially
reduced their migratory behavior following stimulation by antigen-loaded
APCs, WHIMS-T cells maintain their migratory behavior and will form
shorter T/APC interactions (Kallikourdis et al., 2013). As T cells can receive
chemokine-driven costimulatory signals and CXCL12 mediates aberrant
costimulation of WHIM B cells, it will be interesting to see if WHIM
T cells are hypersensitive to chemokine-driven costimulation (Molon
et al., 2005; Roselli et al., 2017). The outcome of T cell antigen stimulation
and the course of the T cell immune response in WHIMS are thus likely
determined by the combined effects of enhanced chemokine-driven costi-
mulatory signaling and reduced APC dwell time.
3.5.9 Leukocyte Adhesion Deficiencies I (CD18) and III (Kindlin-3)

Integral to cell migration and T cell effector function is the ability to adhere
firmly to target cells during IS formation and endothelial cells during diape-
desis (the crossing of endothelial barriers). These firm adhesions are mediated
by cell adhesion molecules called integrins. There are defects in integrins in
two known PIDS. In these leukocyte adhesion deficiencies, migration of
both lymphocytes and neutrophils is affected leading to severe bacterial

infections very early in life that are fatal if left untreated.
In leukocyte adhesion deficiency type I (LADI), biallelic LOF mutations
in ITGB2, encoding the β2 integrin chain CD18 cause loss of the integrins
LFA-1, Mac1, and αXβ2, all of which utilize CD18, from the surface of leu-
kocytes (OMIM 116290). This results in defective adhesion to ICAM1 and
fibronectin (Kishimoto, Hollander, Roberts, Anderson, & Springer, 1987).
LADI patients develop recurrent bacterial infections, perirectal abscesses,
gingivitis, periodontitis, and delayed separation of the umbilical cord pri-
marily related to reduced neutrophil migration (Hayward et al., 1979). Cur-
rently, HSCT is required to correct this fatal PID, though gene therapy may
also be an option (Bauer & Hickstein, 2000).
LADIII is caused by biallelic LOF mutations in the gene encoding
kindlin-3 (OMIM 612840). LADIII is characterized by bleeding tendency
due to platelet adhesion deficiency, neutropenia and lymphocytopenia,
bacterial infections, pneumonia, and sepsis (Malinin et al., 2009;
Pasvolsky et al., 2007; Svensson et al., 2009). Patient cells had defective
integrin-mediated adhesion to and migration on ICAM1 surfaces. LADI
was ruled out due to normal integrin receptor expression. LADIII cells,
in contrast to LADI, show defects in adhesion mediated by multiple integ-
rins that did not depend on CD18, including defects in adhesion mediated
by LFA-1, MAC-1, VLA-4, and αVβ3. Functionally, kindlin-3 regulates
both inside-out and outside-in integrin activation by binding the cytoplas-
mic tail of the β chain and enhancing the recruitment of talin, which links
integrins to the cytoskeleton and stabilizes their activation (Hogg, Patzak,
& Willenbrock, 2011). Kindlin-3 is highly expressed in the immune sys-
tem, whereas kindlin-1 and -2 are expressed in nonimmune tissues,
explaining why kindlin-3 mutations result primarily in an immunological
phenotype. The essential role of integrins in development is reflected by
the early lethality of talin and kindlin-1 knockout mice (Monkley et al.,
2000; Ussar et al., 2008). LADIII was originally attributed to variants in
CALDEG-GEF1 coinherited with Kindlin-3 mutations, though later
studies demonstrated that overexpression of CALDEG-GEF1 could not
rescue the associated phenotype, while reconstitution with Kindlin-3 res-
cued the adhesion and migratory defects (Pasvolsky et al., 2007; Svensson
et al., 2009). This demonstrates the absolute requirement for functional
validation of potentially causal variants, especially in the presence of mul-
tiple candidates that are coinherited with the disease phenotype (Abram &
Lowell, 2009).
3.6 Defects in TFs/TF Regulation

TFs control the rate of genetic transcription generally by binding-specific
DNA sequences or to other DNA-binding proteins. By virtue of the speci-
ficity of binding to different promotor, enhancer, or suppressor DNA
sequence motifs and the expression pattern of the various TFs and signals con-
trolling their activation, TFs play an essential role in determination of tissue-
specific transcriptional patterns. In the immune system, TFs control and
enforce cell fate decisions, cell activation, differentiation, survival, and mem-
ory formation. In this section, we will discuss defects in immune-specific TFs,
or their regulation, that cause various PIDs. Interestingly, several of these PIDs
are caused by haploinsufficiency of the relevant TF, which is likely a function
of tightly controlled TF expression.
3.6.1 FOXP3
A deadly X-linked autoimmune disorder characterized by early onset and
severe IBD/colitis, candidiasis, eczema, atopy, T1DM, and hypothyroidism,
autoimmune cytopenias, lymphadenopathy, and various other autoimmune
conditions is caused by Forkhead box P3 (FOXP3) deficiency, the causative
gene for a similar phenotype in scurfy mice (Bennett et al., 2001; Brunkow
et al., 2001). This condition, termed IPEX or XLAAD disease (OMIM
304790), allowed for the first characterization of the FOXP3 gene, prior
to understanding its role in immune function (Chatila et al., 2000). FOXP3
is now well understood to act as the master TF initiating the development
and maintenance of regulatory T cells (Hori, Nomura, & Sakaguchi, 2003).
Tregs, recruited to the sites of conventional T cell activation downmodulate
the immune response through multiple effector pathways including IL-2
consumption and CTLA-4-mediated inhibition of CD28 ligands on APCs,
among others (Josefowicz, Lu, & Rudensky, 2012). Tregs can also promote
protective immune responses, especially to certain classes of fungi, which
accounts of the candidiasis that occurs in IPEX disease (Pandiyan et al.,
2011). Interestingly, IPEX disease shares several clinical similarities, partic-
ularly colitis, with PIDs associated with other Treg defects such as CTLA-4
deficiency, IL-2 signaling defects, and BACH2 deficiency (see below) thus
highlighting the critical nature of this cell population to the control of
human autoimmunity.
3.6.2 BACH2
Heterozygous mutations in transcriptional repressor BTB and CNC homol-
ogy 2 (Bach2) cause a syndrome of early-onset colitis, splenomegaly,
lymphadenopathy, immunoglobulin deficiency, and respiratory tract infec-

tions called BACH2-related immunodeficiency and autoimmunity (BRIDA)
due to Bach2 haploinsufficiency (Afzali et al., 2017). Patients have specific and
cell-intrinsic defects in CD27+ B cell populations, and the formation of
FOXP3 positive Treg cells which is attributable to reduced Bach2 protein
expression. These features are also observed in bach2 heterozygous mice.
Given the defect in FOXP3 expression, we speculate that defective Treg cell
number or function is the cause of patient colitis and lymphadenopathy in a
partial phenocopy of IPEX disease, while the B cell and antibody defects may
account for the patient’s respiratory infections. These effects are likely due to
loss of Bach2-mediated transcriptional repression of Blimp1 or another Bach2
target, though the full transcriptional profile of Bach2-deficienct patients has
yet to be determined.
3.6.3 BCL11B
An autosomal dominant disease caused by a heterozygous DN variant in
B cell CLL/lymphoma 11B (BCL11B) causes a leaky SCID phenotype with
syndromic features (OMIM 617237). Immunologically the patient had
T cell lymphopenia, absent TREC formation and naı̈ve CD4+ T cell popu-
lations, and impaired proliferative responses (Punwani et al., 2016). BCL11B
encodes for a TF with multiple roles in T cell formation and function
(Avram & Califano, 2014). BCL11B positively regulates T cell lineage com-
mitment while inhibiting pluripotency during thymopoesis, a process that
may determine the T cell-specific immunological phenotype. BCL11B also
aids in the expansion of T cells in the periphery and induction of effector
function, accounting for decreased patient T cell proliferation to mitogen.
3.6.4 NF-κB Family of TFs

The NF-κB family of TFs and their regulatory proteins are critical for the
initiation and control of innate and adaptive immune responses, and over
20 PIDs have been associated with various defects in this pathway. As these
PIDs have been reviewed recently and extensively, we will only discuss
PIDs that were not included in the review by Zhang, Lenardo, and
Baltimore (2017).
3.6.5 RELA
Badran et al. and Comrie et al. have described an autosomal dominant
disorder caused by p65/RELA haploinsufficiency (Badran et al., 2017;
Comrie et al., 2018). In the first report, the authors describe colitis and
mucocutaneous ulcerations, both due to increased TNF-induced epithe-

lial cell apoptosis. These patients benefited greatly pharmacological TNF
inhibition. In contrast, Comrie et al. describe a patient with lymphade-
nopathy, autoimmune cytopenias, and increased T cell proliferation and
effector function. While it may be too early to tell the full clinical spectrum
caused by RELA haploinsufficiency, it should be noted that this variable
clinical expressivity is similar to that described for p50 haploinsufficiecny
(Badran et al., 2017). This can be contrasted with the relatively homog-
enous clinical phenotype of other patients with NF-κB-related PIDs, such
as NEMO patients. This difference may arise because in p50 or RELA
haploinsufficiency, the constellation of affected genes due to insufficient
TF levels may largely depend on infectious history or genetic background,
while patients with defects in NF-κB activators or effectors may more uni-
formly alter NF-κB-dependent transcriptional profile, independent of
confounding determinants.
3.6.6 CARD11
CARD11 mutations cause both autosomal recessive (OMIM 615206) and
autosomal dominant (OMIM 616452) disorders due to LOF and GOF
mutations, respectively (Zhang et al., 2017). GOF mutations result in spon-
taneous CARD11 aggregation and NF-κB activation in B and T cells in
B cell expansion with NF-κB and T cell anergy (BENTA) disease (Snow
et al., 2012). While these GOF variants lead to spontaneous B cell activation,
they result in diminished T cell responsiveness to TCR-mediated stimula-
tion in the absence of appropriate costimulation, a form of stimulation that is
known to cause T cell anergy. Recently an autosomal dominant PID asso-
ciated with CARD11 hypomorphic mutations that cause dominant interfer-
ence with the WT CARD11 allele-dependent activation of NF-κB has been
described (OMIM 617638) (Ma et al., 2017). These patients presented with
severe atopic dermatitis, allergies, elevated IgE, molluscum contagiosum
infection, decreased B cell numbers, and defective T cell activation.
Decreased NF-κB activation leads to reduced CD25 upregulation and pro-
liferation following TCR-mediated T cell stimulation. Why this disease
results in a different clinical phenotype than biallelic CARD11 LOF disease
remains to be seen, though the DN mutations may allow for some residual
CARD11 activity, possibly with altered kinetics, while LOF variants result
in complete loss of CARD11-dependent NF-κB induction downstream of
antigen receptors.
3.7 Defects in Apoptotic Pathways

Immune responses pose a particularly unique challenge in that T and B cells
must expand exponentially to successfully combat infection; however, this
expansion must also be reversed to achieve homeostasis following the res-
olution of infection. This contractile phase is partly due to cytokine
withdrawal-induced apoptosis, in which T cell populations undergo apo-
ptosis due to passive loss of proproliferative/prosurvival signals. Addition-
ally, T cell populations are actively reduced through TCR signals, mediated
in part by TNF-family receptors, which induce apoptosis (Zheng, Li, &
Lenardo, 2017). Additionally, apoptosis must be inhibited in resting cells
to prevent aberrant loss of cell populations. In this section, we will discuss
PIDs associated with defects in the initiation and control of apoptosis and
other forms of regulated cell death.
3.7.1 Somatic Defects in Cytokine Withdrawal-Mediated Apoptosis

(NRAS/KRAS)
Following the clearance of pathogen effector cells no longer produce
enough of the prosurvival/proliferative cytokine IL-2 to maintain the
expanded populations and effector populations undergo growth factor/
cytokine withdrawal-mediated apoptosis, shrinking the peripheral T cell
pool to the size that can be maintained by homeostatic cytokines, such
as IL-7 and IL-15. Somatic heterozygous activating variants in the Ras
homologues NRAS and KRAS cause “RAS-associated leukoproliferative
disorder,” or RALD (OMIM 614470) (Niemela et al., 2011; Oliveira et al.,
2007; Takagi et al., 2011). These mutations lead to a clinical disease similar
to ALPS (see below) with hepatosplenomegaly, autoimmune cytopenias,
and lymphadenopathy caused by defective apoptosis following the acute
removal of IL-2 from T cell in vitro cultures. This was due to NRAS/
KRAS-mediated inhibition of BCL-2-interacting mediator of dell death
(BIM) protein expression and could be rescued by inhibition of farnesyla-
tion, which is required for NRAS and KRAS localization and function, or
PI3K/ERK inhibitors, two downstream RAS effectors. Importantly,
germline activating mutations in NRAS and KRAS can cause Noonan
syndrome, a developmental disorder with no appreciated immunological
phenotype, though these mutations may be less activating than those caus-
ing RALD (Cirstea et al., 2010). It may be that the GOF mutations seen
in RALD would otherwise be lethal if inherited in the germline
configuration.
3.7.2 Death-Induced Signaling Complex Members

(FAS/FASL/Caspase8/Caspase10/FADD)
One of the best described group of related human PIDs associated with apo-
ptotic defects are caused by deleterious variants in the FAS signaling pathway
that gives rise to ALPS. ALPS is characterized by nonmalignant lymphade-
nopathy and splenomegaly, expansion of a CD4/8 αβ T cell population,
development of autoimmune cytopenias, and defective FAS-induced apo-
ptosis in vitro (Price et al., 2014). The FAS receptor (FAS) activation by
FAS ligand (FASLG) results in trimerization of the receptor subunits and
recruitment of Fas-associated protein with death domain (FADD) to the
cytoplasmic tail. FADD bridges FAS to procaspases 8 and 10 to form the
death-induced signaling complex (DISC) leading to the activation of these
caspases and the induction of apoptosis (Peter & Krammer, 2003). FAS and
FASLG are greatly upregulated after T cell activation and serve as an impor-
tant checkpoint on T cell population size. As such, mutations in each
component of the DISC complex have been associated with defective
FAS-induced death and the development of ALPS or ALPS-like conditions
(Rieux-Laucat, Le Deist, & Fischer, 2003).
In the most common form of ALPS, dominant-interfering mutations in
FAS give rise to an autosomal dominant disease due to the incorporation of
defective FAS chains into the FAS receptor trimers (OMIM 601859) (Fisher
et al., 1995; Martin et al., 1999). The majority of these ALPS-causal variants
result in the inability of FAS trimers to recruit FADD, though some inhibit
the palmitoylation-dependent recruitment of FAS to lipid raft microdo-
mains and an inability to fully process caspase-8 despite normal DISC
formation (Cruz et al., 2016; Siegel et al., 2004). Importantly, FAS muta-
tions can arise from both germline and somatic mutations, and thus represent
Mendelian and non-Mendelian forms of the disease, respectively (Oliveira
et al., 2010). Remarkably, for reasons that are obscure, patients with ALPS
due to FAS mutations have very high levels of serum vitamin B12 which is
almost pathognomonic for disease and can be used as a diagnostic tool when
molecular confirmation is difficult to obtain, though direct confirmation
of defects in FAS-mediated apoptosis remains an excellent clinical diagnostic
approach (Lo et al., 2013). Dominant-interfering (OMIM 601859) and
LOF mutations in FASLG cause autosomal dominant and autosomal reces-
sive disease, respectively, though both are much less common than ALPS-
associated FAS mutations (Magerus-Chatinet et al., 2013; Wu et al., 1996).
Mutations in caspase 10 can generate a dominant-interfering protein that
results in an autosomal dominant form of ALPS (OMIM 603909)
(Wang et al., 1999). LOF mutations in caspase 8 also impair FAS-induced

apoptosis as well as TCR- and BCR-induced activation of NF-κB
(Chun et al., 2002; Su et al., 2005). As such, caspase 8-deficient patients suf-
fer from lymphadenopathy, splenomegaly and other features reminiscent of
ALPS combined with recurrent infections due to defects in NF-κB activa-
tion that are not seen in the caspase 10 patients. This unique clinical entity is
called “caspase-8 deficiency syndrome” or CEDS (OMIM 607271). An
autosomal recessive disease with a mild-ALPS phenotype and additional
clinical features including severe bacterial and viral infections, recurrent
hepatopathy and encephalopathy, as well as cardiac malformations results
from biallelic LOF mutations in FADD (OMIM 613759) (Bolze et al.,
2010). Despite the fact that cells from these patients are defective in FAS-
mediated apoptosis only one patient has presented with ALPS-like features
(elevated double negative T cells, high serum FASL, and high IL-10, with
no lymphadenopathy), though the other three patients passed away prior to
evaluation for these conditions. The absence of lymphadenopathy may be
related to the importance of FADD in TCR-mediated T cell proliferation
which likely serves to limit lymphoproliferation and T cell populations in
FADD-deficient patients (Zhang, Cado, Chen, Kabra, & Winoto, 1998).
Additionally, FADD-deficient cells were less susceptible to viral-mediated
cell death and supported higher viral loads upon infection due to defective
IFN signaling. Though not investigated, FADD does play a role in TNF sig-
naling, which may account for the increased susceptibility to bacterial
infections.
3.7.3 XIAP
In a disease whose molecular pathogenesis is related to that of ALPS, LOF
mutations in X-linked inhibitor of apoptosis (XIAP) cause an X-linked
recessive lymphoproliferative syndrome with recurrent infections, EBV
viremia, fever, hemophagocytic lymphohistiocytosis, IBD, and loss of
NKT cells (OMIM 300635) (Aguilar & Latour, 2015; Rigaud et al.,
2006; Worthey et al., 2011). XIAP is thought to act by inhibiting caspase
function downstream of death receptor engagement and can block FAS-
mediated apoptosis (Bratton, Lewis, Butterworth, Duckett, & Cohen,
2002; Holcik & Korneluk, 2001). Functionally, XIAP-deficient patient cells
show increased apoptosis mediated by FAS, TNSF10, and RICD. Thus,
XIAP deficiency results in an inability to control infection through increased
FAS-mediated death of effector cells, and enhanced RICD-mediated death
of antigen-specific cells leading to functional immunodeficiency. XIAP also
plays an important role in pattern recognition receptor signaling, which may

contribute to the susceptibility to infection and early-onset IBD in these
patients.
3.7.4 STK4
Serine/threonine-protein kinase 4 (STK4) is a proapoptotic and antip-
roliferative kinase best known for its involvement in the Hippo signaling
pathway necessary for organ size control (Harvey, Zhang, & Thomas,
2013). This is accomplished by initiating a cellular signaling cascade that ulti-
mately results in the phosphorylation and degradation of the transcriptional
coactivators YAP/TAZ and loss of their proproliferative and antiapoptotic
functions. Additionally, STK4 is required for the phosphorylation and
activation of LC3 during autophagy, thus allowing for the fusion of
autophagosomes with lysosomes (Wilkinson et al., 2015). Biallelic LOF
mutations in STK4 cause an autosomal recessive PID characterized by
atrial septal defects, progressive loss of T and B cells resulting in T/B
lymphopenia, and intermittent neutropenia leading to the development
of recurrent viral, bacterial, and fungal infections (OMIM 614868)
(Abdollahpour et al., 2012). Fas- and staurosporine-induced apoptosis in
T cells and neutrophils, respectively, was dramatically increased in patient
cells compared to controls. This was associated with loss of plasma mem-
brane potential and decreased Forkhead box 03 protein (Foxo3) expres-
sion. As STK4 phosphorylation, activation, and stabilization of Foxo3
are critical for the protection of naı̈ve T cells from the damaging effects
of reactive oxygen species (ROS) in mice, it is likely that STK4 regulation
of Foxo3 is a critical regulator of the human disease (Choi et al., 2009).
Additionally, STK4-deficient patient T cells do not divide well, primarily
due to a massive increase in apoptosis associated with TCR stimulation, as
well as decreased Bcl2 and Foxo1 expression (Nehme et al., 2012).
Together, this suggests that STK4 deficiency results in increased T cell
apoptosis through regulation of STK4 targets outside of the Hippo path-
way, where STK4 normally promotes cell survival by activating Foxo3 and
inducing antiapoptotic and anti-ROS target genes. Notably, activation of
the Hippo pathway in T cells and induction of LC3 activation was not
described in any of these studies, and altered Hippo signaling or decreased
autophagy cannot be ruled out in this disease without further investigation.
Interestingly, STK4 is most highly expressed in naı̈ve T cells, which
implies its loss may sensitize cells to RICD and Fas-mediated apoptosis
in activated T cells as part of the normal immune response.
3.8 Defects in DNA Replication, Accessibility, Repair,

and Telomere Maintenance
As a necessity of function, T and B cells, as well as their hematopoietic pro-
genitor cells, undergo both constitutive division to maintain cell populations
and rapid expansion during selection and immune responses. As such, they
depend heavily on the ability to quickly and efficiently replicate DNA. Dur-
ing periods of such rapid proliferation and DNA synthesis, there is a high
chance for DNA damage to occur. In these cases, repair of DNA damage
is essential for cell cycle progression. Additionally, repeated cellular division
of human immune cells often leads to shortened telomeres, an outcome of
certain lymphoproliferative diseases and the natural aging of the immune
system which characterizes a senescent cellular phenotype in aged T cells
and in some PIDs. Because of this, maintenance of telomere length is critical
to maintain hematopoietic lineages. Finally, in addition to DNA replica-
tion/repair/chromosomal stability, DNA accessibility must also be regulated
to allow for specialized immune cell function. Defects in these processes can
cause various PIDs and are discussed below.
3.8.1 POLEε
DNA polymerase epsilon (POLEε), a DNA polymerase composed of
four subunits, synthesizes the forward strand during conventional DNA
synthesis. Homozygous LOF mutations in POLE1, the catalytic subunit
of POLEε, cause a syndromic immunodeficiency with facial dysmorphism,
livedo, and short stature (FILS syndrome, OMIM 615139) (Pachlopnik
Schmid et al., 2012). Immunologically, patients suffer from recurrent upper
respiratory tract infections, pulmonary infections, bronchiectasis, and
bacterial meningitis. Patients have decreased B cell and immunoglobulin
levels, and a diverse T cell repertoire, but low naı̈ve T cell counts and
decreased T cell proliferation. Patient T cells proliferate poorly in response
to TCR stimulation with fewer cells entering S phase, likely due to stalled/
slow DNA replication. Unlike other cell types, T and B cells express more
POLEε than POLEδ, a related DNA polymerase, suggesting that the T and
B cell specificity of this immunodeficiency is a result of a cell-specific
dependence on POLEε. Biallelic LOF mutations in the second subunit
of POLEε, POLE2, have been described in a patient with facial dysmorph-
isms, combined immunodeficiency, and autoimmunity (Frugoni et al.,
2016). The patient suffered from omphalitis, erythroderma, recurrent
respiratory tract infections, T1DM, hepatomegaly, and hypothyroidism
due to combined B and T cell defects including agammaglobulinemia,

absence of circulating B cells, and T cell lymphopenia with reduced naı̈ve
and expanded effector memory cell populations. Undetectable T cell exci-
sion circles indicated decreased thymic output. The latter likely leads to lym-
phopenia with concomitant expansion and outgrowth of poorly selected
autoreactive cells, thus accounting for the patients’ autoimmune phenotype.
Also observed was a defect in cell cycle progression with reduced percentage
of cells in S phase, similar to POLE1 patient cells.
3.8.2 DNA Ligase 1

While POLEε is required for forward-strand synthesis, DNA ligase 1 is
required for joining of Okazaki fragments in the lagging strand. Biallelic
LOF missense variants in DNA ligase 1 were found in a cell line derived
from a single patient presenting with retarded growth, sun-sensitive facial
erythema, and immunodeficiency characterized by decreased serum immu-
noglobulin levels, poor mitogen responses, and a deadly course of respiratory
tract infections (Webster, Barnes, Arlett, Lehmann, & Lindahl, 1992).
Though immunological samples were not available for further study, it is
likely that DNA ligase 1 and POLEε patients share a related cellular pheno-
type, given the clinical similarities.
3.8.3 MYSM1
Myb like, SWIRM and MPN domain 1 (MYSM1) is an essential compo-
nent of an H2A deubiquitinase complex that coordinates histone H1 disas-
sociation and DNA accessibility, thus allowing for transcription initiation
and elongation (Bahrami et al., 2017). Homozygous LOF mutations in
MYSM1 cause a syndrome of progressive bone marrow failure, immunode-
ficiency, and developmental abnormalities. Immunologically, patients suffer
from recurrent respiratory tract infections, with virtually absent mature and
class-switched B cells, and reduced T and NK cells. Furthermore, T cells
failed to proliferate robustly in response to mitogenic challenge (Alsultan,
Shamseldin, Osman, Aljabri, & Alkuraya, 2013; Bahrami et al., 2017; Le
Guen et al., 2015). MYSM1-deficient cells have increased p38 activation,
cell cycle arrest, and increased apoptosis, presumably due to altered tran-
scriptional activity. In one patient, a spontaneous genetic reversion caused
recovery of all affected hematopoietic lineages, suggesting a strong survival
advantage to WT cells over mutant cells. The exact genetic targets regulated
by MYSM1 remain to be identified and may shed light onto the mechanism
by which MYSM1 deficiency results in increased p38-induced apoptosis.
3.8.4 ATM
Biallelic LOF mutations in ataxia–telangiectasia mutated (ATM) serine/
threonine kinase results in ataxia–telangiectasia (AT), characterized by cer-
ebellar ataxia, telangiectasia, immune defects, and malignancy (OMIM
208900). ATM is recruited to, and activated by, sites of DNA double-strand
breaks and is critical for the DNA damage response comprising inhibition of
cell cycle progression, DNA repair, and apoptosis. The immune defects
accompanying ATM deficiency include thymic hypoplasia, lymphopenia,
reduced T cell numbers, and reduced B cell differentiation (Chopra et al.,
2014; Staples et al., 2008). This is likely due to an inability to respond to
double-strand breaks that occur during thymopoesis and T cell selection,
resulting in apoptosis of T cell progenitors. Interestingly, AT patients present
with a relative increase in γδ T cells compared to αβ T cells (Carbonari et al.,
1990). This may reflect a less severe requirement of γδ T cells for ATM dur-
ing development, though this remains to be seen.
3.8.5 Nibrin
Nibrin (NBN) deficiency results in the autosomal recessive disorder Nijme-
gen breakage syndrome, which is associated with recurrent pneumonia, GI
infections, urinary tract infections, with reduced T cell numbers (OMIM
251260) (Varon et al., 1998). NBN, a component of the Mre11-Rad50-
Nbs1 (MRN) complex, is critical for the response to DNA damage and
maintenance of chromosomal integrity and telomere length (Lamarche,
Orazio, & Weitzman, 2010). Interestingly, NBN activates both ATR and
ATM by phosphorylation during DNA damage responses, placing it
upstream of ATM in the DNA damage response pathway (Lee & Paull,
2004; Stiff et al., 2005). Consistent with this, Nijmegen breakage syndrome
shares similar features to both AT and Seckel syndrome 1, an autosomal
recessive disease characterized by multiple developmental abnormalities,
but no known immunological features, due to hypomorphic ATR variants.
Given the related nature of ATM and ATR kinases, and their respective
roles in DNA damage responses, it is curious as it why ATM and NBN,
but not ATR, deficiencies result in immunological deficiencies.
3.8.6 SMARCAL1
Biallelic LOF variants in SWI/SNF related, matrix-associated, actin-
dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) cause
an autosomal recessive disease characterized by several immunological
defects including neutropenia, lymphopenia, and cytopenias with decreased
T cell numbers and absent mitogenic responses, largely phenocopying
ATM- and NBN-associated disease (OMIM 242900). SMARCAL1 is an

ATP-driven annealing helicase involved in the reannealing of stably
unwound DNA. It may also play an important role in DNA damage by main-
taining genomic integrity at stalled replication forks and is activated by the
ATM kinase, placing it downstream of NBN and ATM in the DNA damage
response (Bansbach, Betous, Lovejoy, Glick, & Cortez, 2009; Boerkoel
et al., 2002; Yusufzai & Kadonaga, 2008). Interestingly, ATR can also phos-
phorylate SMARCAL1 which is necessary for SMARCAL1-mediated
prevention of replication fork collapse during DNA damage response defi-
ciencies (Couch et al., 2013). This suggests that the ATR kinase may also play
an important role in DNA damage response pathways in T cells, which may
simply not be observed in Seckel syndrome I due to the incomplete loss of
ATR function in this disease (OMIM 610600).
3.8.7 NSMCE3
Biallelic LOF variants in NSMCE3 cause an autosomal recessive syndrome
immunologically characterized by thymic hypoplasia, recurrent pulmonary
infections, and eczema (OMIM 617241) (van der Crabben et al., 2016).
NSMCE3-deificient patients have severely reduced T cell numbers, with
reduced T cell responses to multiple mitogenic and recall response stimuli.
NSMCE3 is a critical component of the SMC5/6 DNA repair complex and
supports mitotic proliferation. Defects in both functions likely contribute to
the observed T cell defect, though the exact stages of T cell development and
T cell activation that are affected remain to be elucidated.
It is interesting that not all genetic disorders caused by defects in DNA
repair mechanisms are accompanied by a T or B cell-mediated immunode-
ficiency. Gene mutations affecting many members of the Fanconi anemia
complex cause a bone marrow failure syndrome but are not associated with
decreased T cell counts or function. Similarly, LOF variants in the gene
ERCC6L2 which encodes a novel DNA repair factor, termed Hebo, cause
a bone marrow failure syndrome without an appreciable T or B cell deficit
(Tummala et al., 2014; Zhang et al., 2016). This would suggest that there is a
special role for the ATM checkpoint kinase pathway in mediating T cell
development or function, given the majority of defects in DNA damage
response that cause T cell deficiency fall within this pathway.
3.8.8 Defects in DNA Methylation (DNMT3B, ZBTB24, CDCA7,

and HELLS)
Mutations in four different proteins cause immunodeficiency-centromeric
instability-facial anomalies syndrome (ICF1–4), which is characterized by
a Tlow/NKlow/B+ CVID with reduced immunoglobulin levels and sus-

ceptibility to recurrent respiratory tract infections. Biallelic LOF mutations
in the genes DNA methyltransferase 3 beta (DNMT3B), zinc finger and
BTB domain containing 24 (ZBTB24), cell division cycle-associated pro-
tein 7 (CDCA7), and helicase, lymphoid specific (HELLS) are responsible
for ICF1–4, respectively (OMIM 242860, 614069, 616910, and 616911)
(de Greef et al., 2011; Hansen et al., 1999; Thijssen et al., 2015). While
DNMT3B, ZBTB24, and HELLS play important roles in de novo DNA
methylation and maintenance of DNA methylation, accounting for their
shared phenotype, CDCA7’s best known role is as a Myc-induced positive
regulator of Myc activity, whose activity can be downregulated by Akt-
mediated phosphorylation (Gill, Gabor, Couzens, & Scheid, 2013; Xu
et al., 1999). Interestingly, Myc can repress transcription by recruiting
the DNA methyltransferase DNMT3A, a close homologue of DNMT3B
(Brenner et al., 2005). This raises the possibility that all four proteins
function within the same pathway, DNMT3B, ZBTB24, and HELLS
directly regulating DNA methylation, while CDCA7 is required for
Myc-dependent recruitment of one or more of these repressors. While
the transcriptional repercussions of deficiencies in these proteins are likely
to overlap with one-another, the mediators of the disease phenotype
remain largely unknown.
3.8.9 Defects in Telomere Maintenance (DKC1 and RTEL1)

Telomeres are the hexapeptide repeats on the ends of chromosomes and
associated protein complexes. Proper-telomere length is an actively
maintained property and with multiple cell divisions resulting in telomere
shortening opposed by the action of a family of proteins called telomerases
that add the hexapeptide repeats to the 30 end of telomeres. Proper length
maintenance is critical, especially in quickly dividing cells, because telomeres
that become too short result in the initiation of apoptosis or cellular senes-
cence (Hodes, Hathcock, & Weng, 2002). In fact, short telomeres are a
marker of multiple PIDs associated with hyperactivation and accumulation
of senescent cells, such as PASLI. First identified in a screen of patients with
X-linked recessive dyskeratosis congenital (XL-DC, OMIM 305000) and
short telomeres, dyskerin pseudouridine synthase (DKC1) is an obligatory
component of the telomerase complex (Heiss et al., 1998; Mochizuki,
He, Kulkarni, Bessler, & Mason, 2004). In Hoyeraal–Hreidarsson syn-
drome, a severe early-onset form of XL-DC, a missense mutation in
DKC1 was correlated with a complete absence of B and NK cells, with mild
T cell defects (Cossu et al., 2002). Defects in another protein involved in

telomere maintenance, RTEL1, causes decreased telomere length, bone
marrow failure, and a severe B cell immunodeficiency, again with mild
T cell defects (OMIM 615190) (Le Guen et al., 2013; Walne, Vulliamy,
Kirwan, Plagnol, & Dokal, 2013). In a review of dyskeratosis congenital
focused on immunological phenotypes, roughly 50% of patients had
decreased T cell numbers (Solder, Weiss, Jager, & Belohradsky, 1998). Lon-
gitudinal studies in these patients may be particularly interesting, because
telomere length in peripheral T cell populations is well known to shorten
during the natural aging process. Thus, patients with DKC1 or RTEL1
mutations may have exacerbated T cell telomere loss and acquisition of senes-
cent T cells as they age, even if this was not observed upon initial clinical
presentation.
As with mediators of the DNA damage response, many more genetic
defects in telomere maintenance result in bone marrow failure and
cytopenias with no appreciated T or B cell defects. One possible reason
for the presence of bone marrow failure, but not T or B cell defects, is that
the progressive disease may largely take place after the development of a
naı̈ve T and B cell repertoire sufficient to fill the peripheral compartments.
3.9 Vesicular Trafficking and Protein Sorting

Mutations in genes that regulate the formation, translocation, fusion, or
function of lytic granules can commonly impact the function of multiple
immunological subsets, including the cytolytic activity of CD8+ cytotoxic
T lymphocytes (CTLs), and ultimately cause PIDs with overlapping clinical
features.
3.9.1 HPS2
An autosomal recessive form of Hermansky–Pudlak syndrome with immu-
nodeficiency, including recurrent lung infections, recurrent bacterial infec-
tions, thrombocytopenia, with neutrophil, NK, and CTL functional defects
(HPS2) is caused by biallelic LOF mutations in AP3B1 encoding the beta-
3A subunit of the adaptor protein (AP)-3 complex (OMIM 608233)
(Dell’Angelica, Shotelersuk, Aguilar, Gahl, & Bonifacino, 1999; Huizing
et al., 2002; Jung et al., 2006). Deficiency of this subunit results in dimin-
ished protein stability of the other complex subunits. Loss of the AP-3 com-
plex causes enlargement of lytic granules in CD8+ T cells and their inability
to move along microtubules to coalesce at the microtubule organizing
center (MTOC) prior to MTOC polarization (Clark et al., 2003). This step
is essential for granule delivery to the IS and failures to coalesce at the

MTOC abolishes CTL cytolytic capacity. While CTL deficiency likely
accounts for the immunodeficiency seen in HSP2 cases, trafficking of lyso-
somes in general is also perturbed, accounting for the wider HPS phenotype.
While mutations in AP3B1 have been described in HPS2, it remains possible
that mutations in other subunits of the AP-3 complex will cause a similar
phenotype.
3.9.2 Lytic Granule Functional Deficiencies (Perforin-1, UNC13,

MUNC13-4, Syntaxin-11, MUNC18-2, RAB27a, and LYST)
Familial hemophagocytic lymphohistiocytosis (FHL) is a hyperinflammatory
state caused by the uncontrolled activation of lymphocytes and macro-
phages. In total, there are six known genetic causes of FHL, all encoding
protein products critical for NK and CTL cytolytic function (OMIM
PS267700). These proteins each provide a nonredundant function in the
synthesis, trafficking, docking, priming, fusion, or effector function of cyto-
toxic granules, and loss of any single one results in defects in cytolytic activ-
ity. The inability to kill target cells results in prolonged APC/T cell contacts,
hyperactivation and proliferation of CTLs, secretion of large quantities of
IFNγ, macrophage activation, and cytokine storm, which together account
for the patient phenotype (Sepulveda & de Saint Basile, 2017). FHL2 is an
autosomal-recessive form of disease caused by biallelic mutations in
Perforin-1, a pore-forming molecule packaged in cytolytic granules and
excreted into the synaptic space where it acts on target cell membranes to
initiate CTL-mediated killing (Podack et al., 1988; Stepp et al., 1999;
Voskoboinik, Whisstock, & Trapani, 2015). Biallelic LOF variant in
UNC13D, encoding Munc13-4, cause FHL3, where Munc13-4 plays an
essential role in lytic granule fusion, but not granule polarizing or docking
with the IS (Feldmann et al., 2003; Santoro et al., 2006). Munc13-4 is a
Rab27a effector essential for a priming step prior to lytic granule fusion,
likely by mediating Ca2+-dependent SNAP (soluble NSF attachment pro-
tein) receptor (SNARE) complex formation (Boswell et al., 2012; Menager
et al., 2007). FHL4 is caused by LOF mutations in the gene encoding
Syntaxin-11, an atypical member of the q-SNARE family required for
SNARE complex formation and lytic granule fusion (Kogl et al., 2013;
Muller et al., 2014; zur Stadt et al., 2005). Syntaxin-11 interacts with
Munc18-2, whose loss causes FHL5 (Cote et al., 2009; zur Stadt et al.,
2009). Munc18-2 is necessary for the localization of syntaxin-11 to the
plasma membrane (Dieckmann, Hackmann, Arico, & Griffiths, 2015).
Some causal mutations in both Syntaxin-11 and Munc18-2 abrogate the

interaction between the two proteins, highlighting the requirement for both
proteins in lytic granule function. Biallelic LOF variants in Rab27a and
LYST also cause FHL in the context of Griscelli syndrome (OMIM
607624) and Chediak–Higashi syndrome (CHS, OMIM 214500), respec-
tively (Menasche et al., 2000; Nagle et al., 1996). Rab27a, in addition to
regulating Munc13-4, is required for the movement of lytic granules from
the polarized MTOC to the plasma membrane, the last step prior to granule
docking at the plasma membrane (Stinchcombe et al., 2001). The function
of LYST, a large beach domain containing protein, remains poorly under-
stood, though it may play important roles in regulating the general biogen-
esis, structure, and turnover of endosomal compartments, including lytic
granules (Holland, Torgersen, Sandvig, & Simonsen, 2014; Sepulveda
et al., 2015). Interestingly, LYST deficiency in CHS is also associated with
defects in CTLA4 trafficking, where it accumulates in large endosomes, sug-
gesting a possible role of CTLA4 deficiency in the lymphoproliferation seen
in CHS (Barrat et al., 1999).
3.9.3 LRBA
An autosomal recessive disorder caused by LOF mutations in the LPS-
responsive beige-like anchor protein (LRBA) leading to complete loss of
protein expression was first identified in a large consanguineous family with
early onset IBD (EO-IBD) and combined immunodeficiency with autoim-
munity (OMIM 614700). Patients with LATAIE (LRBA deficiency with
autoantibodies, Treg defects, autoimmune infiltration, and enteropathy)
disease had various combinations of early onset diarrhea, autoimmune pan-
cytopenia, EBV-associated lymphoproliferation, and vitamin B12 deficiency.
While some patients had low B cell and IgG/IgA levels, this was not consis-
tent across all patients (Alangari et al., 2012). Further characterization of
additional LATAIE patients expanded the clinical phenotype to include
chronic lung infections and bronchiectasis and highlighted the importance
of LRBA for B cell activation and class-switched antibody secretion
(Lopez-Herrera et al., 2012). LRBA deficiency also caused decreased num-
bers of FOXP3+ Tregs that had lower expression of the Treg functional
markers CTLA4/CD25 and impaired inhibitory function. This was associ-
ated with increased memory T cell accumulation (Charbonnier et al.,
2015). Extended analysis of a large cohort of LATAIE patients demonstrated
that most patients develop some combination of immune dysregulation,
lymphadenopathy, infections, and hypogammaglobulinemia with defects in
Tregs, B cell class switching, and plasmablast formation (Gamez-Diaz et al.,

2016). Lo et al. discovered that LRBA associates with CTLA4 via the YVKM
motif in the CTLA4 cytoplasmic tail and prevents its proteolytic turnover.
Specifically, LRBA prevents the association of CTLA4 with AP-1, thus
restricting its localization to recycling endosomes (Lo et al., 2015). In the
absence of LRBA, CTLA4 is shuttled preferentially to the lysosomes where
it is degraded. Critically, pulmonary lymphocytic infiltrates responded favor-
ably to abatacept therapy, suggesting that the decrease in CTLA4 expression
was responsible for the autoimmune symptoms. Interestingly, defects in
autophagy and mTOR activation were also demonstrated in LRBA-deficient
cells, suggesting additional roles of LRBA in regulation of the immune
response (Charbonnier et al., 2015; Lopez-Herrera et al., 2012). Further anal-
ysis of LRBA deficiency will be required to understand how LRBA mediates
its B cell-intrinsic functions and to what degree this is influenced by the loss of
CTLA4 and consequent dysregulation of T cell immunity vis-à-vis the defects
in autophagy and mTOR activation.
3.9.4 UNC119
Recently a 32-year-old female was described with an autosomal dominant
disease consisting of shingles, oral hepatic lesions, otitis media, persistent
fungal infections, and pulmonary infections with an idiopathic CD4+
T cell lymphopenia (OMIM 615518). The patient’s disease was associated
with a heterozygous dominant-interfering mutation (G22V) in the unc-
119 homologue A protein (UNC119) (Gorska & Alam, 2012). UNC119
acts as a trafficking chaperone for multiple proteins and is involved in endo-
some recycling through the activation of Rab11 (Jaiswal et al., 2016;
Kobayashi, Kubota, Mori, McLaren, & Inana, 2003; Zhang et al., 2011).
In T cells, UNC119 is recruited to the IS and interacts specifically with
Lck via a proline-rich motif in UNC119 and the SH3 domain of Lck in
an activation-dependent manner. This interaction is critical for TCR stim-
ulation as the UNC119/Lck interaction directly contributes to the activa-
tion of this keystone src kinase during TCR signaling (Gorska, Stafford,
Cen, Sur, & Alam, 2004). UNC119 is also critical for the proper trafficking
of Lck to the IS since Lck will accumulate in Rab11+ endosomes in the
absence of UNC119. This defect is likely due to loss of UNC119-mediated
Rab11 activation and it can be overcome through the expression of consti-
tutively active Rab11 or UNC119 reconstitution (Gorska, Liang, Karim, &
Alam, 2009). The G22V mutation is unable to bind Lck, presumably
because the mutation is directly N-terminal to the polyproline motif
required for Lck association and activation. In overexpression systems, and

in patient cells, G22V UNC119 caused decreased membrane targeting of
Lck and increased Lck localization to Rab11+ endosomes, leading to
reduced Lck activation and poor proliferative responses of patient T cells
(Gorska & Alam, 2012). The two functions (UNC119-dependent Lck
recruitment and activation of Rab11) may be linked as UNC119-mediated
Lck recruitment to Rab11 endosomes may initiate Src kinase-dependent
activation of Rab11 (Lee et al., 2013). Interestingly, heterozygous LOF
UNC119 mutations cause cone-rod dystrophy and retinal degeneration
without any immunological phenotype, suggesting multiple disease pheno-
types depending on the nature of the UNC119 mutation (Kobayashi et al.,
2000). Given how important proper trafficking and activation of Lck is to
T cell function, it will be interesting to see if mutations in other proteins
involved in the regulation of Rab11+ vesicular trafficking (such as family
of Rab11-interacting protein (FIP)3) are associated with undiscovered PIDs
(Bouchet et al., 2016, 2017).
3.10 Defects of Ubiquitination

3.10.1 ITCH
Ubiquitination of proteins can target them for proteasomal degradation,
mediate protein–protein interactions, or alter activity and cellular localiza-
tion. As such, proper regulation of ubiquitination is essential for cellular
function and dysregulation of this pathway has been implicated in several
human diseases (Popovic, Vucic, & Dikic, 2014). Several patients have been
identified from an Amish cohort with homozygous truncating mutations in
the E3 ubiquitin ligase, ITCH (OMIM 613385) (Lohr et al., 2010). These
patients present with hepatosplenomegaly, chronic lung disease, and recur-
rent diarrhea with severe lymphocytic infiltrates. While more extensive
immunophenotyping of T cells and other immune cell types is required
to confirm T cell defects in humans, ITCH-deficient mice develop skewed
T cell responses and T cell-dependent autoimmunity (Fang et al., 2002;
Parravicini, Field, Tomlinson, Basson, & Zamoyska, 2008). Thus it is likely
that these patients will have some level of T cell dysfunction.
3.11 Defects of Glycosylation

Proper glycosylation, the enzymatic process of attaching a carbohydrate to a
molecule, is generally essential to the efficient functioning of the recipient.
In the case of proteins, glycosylation can serve to ensure proper protein
folding, stability, and function. As such, various immunodeficiencies have

been identified that affect the glycosylation pathway (Monticelli, Ferro,
Jaeken, Dos Reis Ferreira, & Videira, 2016).
3.11.1 MAGT1
In 2011, our lab identified hemizygous LOF mutations in the X-linked gene
encoding magnesium transporter 1 (MAGT1) in patients with chronic EBV
infection and lymphoma with reduced naı̈ve T cells, low CD4+ T cell
counts, and defective CTL cytotoxicity accompanied by deficits in NKG2D
glycosylation and expression (X-linked magnesium deficiency with EBV
and neoplasia, XMEN disease, OMIM 300853) (Chaigne-Delalande
et al., 2013; Li et al., 2011). MAGT1-deficient cells have reduced basal intra-
cellular Mg2+ levels and are defective in a TCR-mediated Mg2+ flux. This is
consistent with MAGT1’s described role as a magnesium transporter
(Goytain & Quamme, 2005). The MAGT1 protein regulates T cell activa-
tion at an early stage, specifically at the level of PLCγ phosphorylation and
further downstream processes including p65 nuclear translocation, calcium
flux, and activation marker upregulation. As previously mentioned, defects
in Itk/PLCγ may preferentially lead to susceptibility to EBV infections,
which further implicate this molecular pathway in the pathogenesis of
XMEN disease. Interestingly, Mg2+ supplementation in vitro and in vivo
rescues NKG2D expression, CTL function, and resulted in reduced EBV
viral load, but does not affect early TCR-mediated signaling defects
(Chaigne-Delalande et al., 2013). These results are consistent with MAGT1
regulating both a stable basal and transient TCR-induced pool of free Mg2+,
with the former being important for NKG2D glycosylation/stability
and rescued by Mg2+ supplementation and the latter important for TCR
proximal signaling events and not rescued by Mg2+ supplementation. Inter-
estingly, however, MAGT1 is a homologue of yeast OST3 and, along with a
third homologous protein (TUSC3), performs an accessory function to
STT3B-mediated glycosylation (Cherepanova & Gilmore, 2016; Kelleher
& Gilmore, 2006). Thus, the MAGT1 protein may directly modulate gly-
cosyltransferase activity independently, or in addition to, its role in Mg2+
regulation. This raises the additional question of whether MAGT1 is itself
a magnesium channel or indirectly regulates Mg2+ levels by assisting in
the glycosylation of an as-of-yet unidentified channel. Why exactly
MAGT1 deficiency results in such a narrow clinical phenotype is incom-
pletely understood, though it may be possible that TUSC3, a highly homol-
ogous protein encoded on chromosome 8, can compensate in other tissues
in XMEN patients, thus confining the disease mainly to specific cells of the
immune system.
3.11.2 PGM3
The conversion of GlcNAc-6-P into GlcNAc-1-P is catalyzed by phospho-
acetylglucosamine mutase (PGM3) and is required for the synthesis of
UDP-GlcNAc, a critical nucleotide sugar donor for multiple glycosylation
pathways. Several studies have identified biallelic LOF mutations in PGM3
in an autosomal recessive PID characterized by recurrent bacterial, fungal,
and viral infections, allergies, and T cell lymphopenia (OMIM 615816)
(Lundin et al., 2015; Sassi et al., 2014; Stray-Pedersen et al., 2014b;
Zhang et al., 2014b). Patients show reduced UDP-GlcNAc and decreased
formation of complex N-glycans. Patient T cells skew toward Th2-type
responses possibly accounting for the increased prevalence of allergies in
patients with PGM3 deficiency. Why PGM3 deficiency causes specific
T cell lymphopenia is incompletely understood, however, it is known that
T cells upregulate UDP-GlcNAc and O-GlcNAcylation by O-GlcNAc
glycosyltransferase (OGT) upon activation (Swamy et al., 2016). Addition-
ally, the deletion of OGT in the thymus results in a strong block in thymic
development while its deletion in ex vivo proliferating T cells resulted in
diminished proliferation due to reduced c-Myc expression. Therefore,
PGM3 deficiency may reduce O-GlcNAcylation due to decreased UDP-
GlcNAc which could inhibit c-Myc in PGM3-deficient patients. Supple-
mentation with exogenous GlcNAc increases intracellular UDP-GlcNAc
levels in PGM3-deficient cells thereby bypassing PGM3 in the catalytic
pathway and rescuing the deficient function in ex vivo cell cultures. Hence,
this may represent a useful therapeutic strategy in PGM3 deficiency (Zhang
et al., 2014b).
3.11.3 EXTL3
Biallelic LOF mutations in exostosin-like glycosyltransferase 3 (EXTL3)
lead to an autosomal recessive disease of skeletal dysplasia and immunode-
ficiency characterized by T cell lymphopenia, expansion of a senescent
CD8+ T cell population, reduced TCR-mediated T cell activation, Omenn
syndrome, eosinophilia, and hyper-IgE (OMIM 617425) (Guo et al., 2017;
Notarangelo, 2017; Oud et al., 2017; Volpi et al., 2017). These defects were
linked to a decreased capacity for HSC differentiation and decreased thymo-
poesis, as well as reduced IL-2-dependent signaling. EXTL3 is an α1,4-N-
acetylglucosaminyltransferase that is involved in heparan sulfate biosynthesis
through glycan chain initiation and elongation. How exactly altered heparin
sulfate composition observed in patient cells may be regulating these various
processes remains to be seen, though it should be noted the HSCT was cura-
tive, marking the affected pathway as a T cell-intrinsic defect. It is possible that
modification of certain signaling proteins by heparin sulfate can modulate their
signaling capacity. Precedence for this idea is demonstrated by the require-
ment of CD47 modification by heparan sulfate for thrombospondin-1 to
inhibit T cell activation (Kaur et al., 2011).
3.12 Defects in Autophagy and Protein Turnover

Autophagy, and more generally the turnover of cellular components, is
dynamically regulated during T cell responses and is critical for T cell sur-
vival during multiple phases of the immune response including the contrac-
tion phase, effector to memory transition, and memory maintenance.
Ultimately, defects in autophagy lead to the inability to control of chronic
infections (Xu et al., 2014). Currently, there are two described PIDs with
defects in autophagy and protein turnover arising from either EPG5 or
TPP2 deficiency, respectively.
3.12.1 EPG5
Biallelic LOF mutations in the gene encoding Ectopic P-granules autophagy
protein 5 homologue (EPG5) leads to a variable PID characterized by recur-
rent viral, bacterial, and fungal infections, and profound CD4+ T cell
lymphopenia, coupled with multiple syndromic features (slow growth,
microcephaly, cleft palate, and heart defects with corpus callosum agenesis,
cataracts, and cardiomyopathy), termed VICI syndrome (OMIM 242840)
(Byrne et al., 2016; Cullup et al., 2013; Ehmke et al., 2014). EPG5 defi-
ciency causes the accumulation of impaired autolysosomes due to defects
in the final maturation step of autophagosomes to autolysosomes necessary
for cargo degradation (Tian et al., 2010). While variable immunodeficiency
has been associated with VICI syndrome, it is not known if EPG5 regulates
T cell memory formation or maintenance and if this is an important aspect of
the immunodeficiency. Interestingly, patient fibroblasts show altered Akt/
mTOR signaling, but this has not been evaluated in patient T cells where
the mTOR pathway is critical for T cell effector responses. Further inves-
tigation into the PID associated with VICI syndrome would be necessary to
understand EPG5’s role in T cell development, effector responses, and
memory formation.
3.12.2 TPPII
During turnover in both the proteasome and the lysosome/autophagosome,
proteins are first cleaved into long oligopeptides with subsequent processing
by N-terminal tripeptide cleavage by tripeptidyl peptidases (Tomkinson,
1999). Biallelic LOF mutations in tripeptidyl peptidase II (TPPII) results
in a recessive disease of immunodeficiency, autoimmunity, and develop-
mental delay termed “TPPII-related immunodeficiency, autoimmunity,
and neurodevelopmental delay with impaired glycolysis and lysosomal
expansion” (TRIANGLE disease) (OMIM 190470). Patients develop
recurrent viral and bacterial infections, cytopenias, lupus-like disease in
the central nervous system, early-onset Evan’s syndrome, and autoimmune
hepatitis (Lu et al., 2014). Patient CD8+ T cells largely expressed a senes-
cent phenotype with poor proliferative responses (Stepensky et al., 2015).
TPPII was observed to be essential for protein turnover and regulation of
free amino acid levels as well as maintenance of baseline mTOR signaling.
Interestingly, TPPII deficiency/inhibition resulted in increased lysosome
biogenesis and modestly increased autophagosome formation in an appar-
ent compensation for the deficiency in free amino acids. In turn, this leads
to a secondary proteolytic loss of hexokinase 2 and decreased glycolysis/
effector function in TPPII-deficient/inhibited cells. Why TPPII deficiency
results in autoimmunity and a population of activated senescent CD8+
T cells, especially given reduced mTOR activation in TPPII-deficient cells,
requires further investigation. Whether or not TPPII is important for mem-
ory formation or viral control in chronic infection remains to be elucidated,
as does the exact role of autophagy and protein turnover in these processes.
3.13 Defects in Metabolic Pathways

Throughout ontogeny and during the mature lifecycle in the immune sys-
tem, the metabolic properties of T cells are meticulously controlled to best
support the cellular demands for function (Buck, O’Sullivan, & Pearce,
2015). Additionally, some metabolites that are produced at sites of rapid pro-
liferation and apoptosis, such as in bone marrow and thymic environments,
are toxic to lymphocytes and must be properly disposed of in order to ensure
optimal lymphocyte survival and function. In the next section, we will dis-
cuss PIDs related to defects in metabolic pathways.
3.13.1 CTPS1
Cytidine 50 triphosphate synthase 1 (CTPS1) is critical for the formation of
CTP, a precursor of DNA, RNA, and phospholipids (Kursula et al., 2006).
While this protein’s function is obvious, it did not have a selective function
in the immune system until WES sequencing identified biallelic LOF muta-
tions in CTPS1 as the cause of an autosomal recessive immunological
disorder (OMIM 615897) (Martin et al., 2014). Patients presented with
recurrent viral and bacterial infections, including severe EBV infection.
Infectious susceptibility was traced to a T cell-specific lymphopenia, with
specific loss of naı̈ve T cells, increased memory T cells, and complete
absence of invariant T cell populations. Interestingly, CTPS1 expression
is low in all cell types, but is specifically and massively upregulated in
antigen-stimulated T cells within days after activation. This implies that
it is a special prerequisite during this period of rapid cell growth and divi-
sion. T and B cell proliferation following in vitro antigen stimulation was
markedly decreased in the absence of CTPS1. Critically, supplementation
of T cells with CTP or cytidine rescued the T cell proliferation defect, sug-
gesting this disorder could be circumvented by providing exogenous end
products of CTPS1 function (Martin et al., 2014). As the plasma membrane
is generally impermeable to nucleoside triphosphates, the use of concentra-
tive or equilibrative nucleoside transporters is required for the uptake of
these biomolecules. Interestingly, several of these transporters are regulated
during immune cell activation and may ultimately prove to be the source of
as-of-yet undefined PIDs (Pastor-Anglada et al., 2001).
3.13.2 AK2
Adenylate kinase 2 (AK2) catalyzes the conversion of ADP to ATP and
AMP, and is thus crucial for the de novo biogenesis of AMP (Noma,
2005). Biallelic LOF mutations in AK2 causes reticular dysgenesis, a severe
SCID phenotype with absence of granulocytes, severe lymphocyte defi-
ciency, hypoplasia of the thymus and lymph nodes caused by an early arrest
in myeloid lineage development and lymphoid maturation with loss of
almost all major immune cellular subsets (OMIM 267500) (Lagresle-
Peyrou et al., 2009; Pannicke et al., 2009). This was traced back to an
increase in spontaneous apoptosis related to defects in mitochondrial func-
tion, oxidative phosphorylation, and ROS production due to altered
homeostasis of ADP, ATP, and AMP (Six et al., 2015).
3.13.3 ADA
Adenosine deaminase (ADA) catalyzes the irreversible deamination of aden-
osine and deoxyadenosine in the purine catabolic pathway. ADA deficiency,
which causes an accumulation of dATP, was first recognized to cause a
SCID phenotype in the early 1970s (OMIM 102700) (Blackburn &

Kellems, 2005). Since then, it has been appreciated that ADA deficiency
can cause a range of clinical severity that largely depends on the quantity of
residual ADA activity (Hershfield, 2003). In the absence of ADA, adenosine
and deoxyadenosine build up in the bone marrow and thymus where these
metabolites cause increased apoptosis along with inhibition of the activation
and expansion of T lymphocytes (Bradford, Moretti, Carbonaro-Sarracino,
Gaspar, & Kohn, 2017). Treatment for ADA–SCID has traditionally included
HSCT, but has now been expanded to include a gene replacement therapy
called Strimvelis, underscoring the growing importance of individualized
genetic medicine for monogenic disorders.
3.13.4 PNP
Biallelic LOF mutations in purine nucleoside phosphorylase (PNP) cause an
autosomal recessive SCID phenotype with frequent bacterial and viral infec-
tions, lymphopenia, a small or absent thymus, and decreased T cell prolif-
eration and function, often accompanied by autoimmune disease (OMIM
613179) (Edwards, Hopkinson, & Harris, 1971; Markert, 1991). PNP cat-
alyzes inosine to hypoxanthine and guanosine to guanine, which ultimately
get degraded to uric acid. In the absence of PNP, there is a build-up of
deoxy-GTP which proves highly toxic to T cell populations, thus leading
to the T cell-specific deficiency.
3.13.5 MTHFD1
Biallelic LOF variants in methylenetetrahydrofolate dehydrogenase,
cyclohydrolase, and formyltetrahydrofolate synthetase 1 (MTHFD1) result
in an autosomal recessive PID characterized by recurrent lung infections,
moniliasis, liver fibrosis, septic arthritis, multiple cytopenias, and low T,
B, and NK cells, which are sometimes accompanied by autoimmunity
(OMIM 617780) (Burda et al., 2015; Keller et al., 2013; Watkins et al.,
2011). MTHFD1 is an enzyme that catalyzes three separate steps in folate
metabolism by processing single carbon folate derivatives utilizing three sep-
arate protein domains (Hum, Bell, Rozen, & MacKenzie, 1988). Vitamin
B12 and folate replacement in MTHFD1-deficient patients resulted in
reconstitution of T and B cell counts, and rescued response to mitogenic
stimuli. Thus, in metabolic disorders, such as MTHFD1 deficiency, supple-
mentation of patients with end products of the pathway can overcome the
endogenous deficiency in metabolite synthesis, though this likely depends
on metabolite bioavailability.
3.13.6 TFRC
Biallelic LOF mutations in the transferrin receptor (TFRC), which is critical
for iron uptake, results in an autosomal recessive PID characterized by mild
anemia, intermittent neutropenia, and defective B and T cell activation and
memory formation, despite normal lymphocyte counts (OMIM 616740)
(Jabara et al., 2016; Lo, 2016). The identified TFRC mutation results in
overall increased TFRC protein production and cell surface expression
and, concomitantly, reduces receptor internalization following stimula-
tion. The addition of iron citrate, which saturates the transferrin receptor
and allows iron internalization independent of TFRC rescued T and B cell
proliferation and class switching defects. This study illustrates how the
molecular investigation of PIDs reveals previously unknown roles of
known proteins in immune function, as this was the first appreciated role
of TFRC in host defense. While TFRC deficiency is the first known PID
associated with cell-intrinsic iron uptake, it has long been known that iron
deficiency results in poor T and B cell responses and decreased cellularity
(Bowlus, 2003).
3.14 Altered T Cell Effector Function in Complement

Deficiencies
3.14.1 C3
While the complement pathway is well recognized to play an essential role
in host defense, we have only recently begun to understand the role of com-
plement proteins in the regulation of adaptive immune responses by mod-
ulating T cell effector function (Hess & Kemper, 2016; Liszewski et al.,
2013). C3a, C3b, and C5a, along with their respective receptors C3aR,
CD46, and C5aR1 influence the survival, metabolic program, and effector
differentiation of T cells during stimulation. Interestingly, T cells from
C3-deficient patients (OMIM 613779) show reduced IFNγ and IL-2 pro-
duction, which is likely dependent on T cell-intrinsic C3 production.
3.14.2 CD55
The significance of complement signaling in the function of human T cells
was demonstrated by Ozen et al. who recently described CD55 deficiency
with hyperactivation of complement, angiopathic thrombosis, and protein-
losing enteropathy (the CHAPLE syndrome) (Ozen et al., 2017). The
CD55-deficient patients also exhibited T cell-intrinsic defects in IL-10 pro-
duction and enhanced TNF production (OMIM 226300) (Ozen et al.,
2017). CD55 is a cell surface complement inhibitory protein that is
expressed on a wide range of cells including lymphocytes. It controls the

level of opsonin and anaphylatoxin split products produced from the C3
and C5 proteins. Interestingly, while the enhanced TNF production was
dependent on C5aR1, the IL-10 defect was not rescued by complement
inhibition, and may reveal a CD55-dependent costimulatory pathway that
is absent in patient cells. Importantly, administration of Eculizumab, a
monoclonal antibody that prevents complement protein C5 cleavage, dra-
matically alleviates many symptoms related to CD55 deficiency, suggesting
that the patient disease is, in-fact, mediated by overt complement activation
(Kurolap et al., 2017).
3.15 Unknown Mechanism

In some cases, the causal gene of an immunodeficiency may be known while
its biological purpose is not well understood. Such cases are excellent work-
ing examples of forward genetic screens of nature identifying genes of
unknown function that are critical to human health and disease. In the next
section, we will briefly describe two PIDs associated with mutations in genes
whose function remains poorly understood.
3.15.1 SP110
Biallelic LOF mutations in SP110 nuclear body protein (SP110) cause an
autosomal recessive disorder with veno-occlusive disease and immunodefi-
ciency characterized by infection susceptibility, low T cell numbers, hyp-
ogammaglobulinemia, and decreased germinal center and plasma cell
formation (OMIM 235550) (Roscioli et al., 2006; Wang, Ong, Roscioli,
Cliffe, & Church, 2012). In its best known function, SP110 associates with
the nuclear body and may either act as a nuclear hormone receptor or as an
activator of NF-κB under certain circumstances, though neither role has
been well validated (Bloch et al., 2000; Leu et al., 2017).
3.15.2 TTC7A
Biallelic mutations in tetratricopeptide repeat domain 7A (TTC7A) cause an
autosomal recessive combined syndrome of immunodeficiency, autoimmu-
nity, and intrinsic GI defects (OMIM 243150) (Chen et al., 2013). These
patients have reduced B and T cell populations with poor antibody produc-
tion and T cell proliferation to mitogen. Patient intestinal organoids showed
defects in polarity formation with increased activation of RhoA targets—
pERM and phosphorylated myosin light chain. Rho-associated protein
kinase (ROCK) inhibition resulted in reversion of polarity, suggesting
increased RhoA signaling may be the cause of patient disease (Bigorgne et al.,
2014). Patient PBMCs also have increased spontaneous phosphorylation of
ERM proteins and MLC, with increased TCR- or integrin-mediated
T cell spreading. Additionally, patient cells express decreased chemokine
receptors and migrated poorly compared to control cells. Finally, patient
T cells were hyperproliferative, which could be corrected by ROCK inhi-
bition (Lemoine et al., 2014). In a known function, TTC7A regulates PI4KA
localization, with TTC7A knockdown resulting in poor PIP production and
mutant TTC7A associating poorly with PI4KA (Avitzur et al., 2014). Despite
these strong hints, the precise effect of TTC7A on RhoA and PI4KA func-
tion, and if these represent separate or linked biochemical functions of
TTC7A, are undetermined.
4. CURRENT CHALLENGES/APPROACHES AND FUTURE

CONSIDERATIONS
One of the greatest challenges facing clinicians and scientists in the
identification and study of causal variants in PIDs, and genetic disease in gen-
eral, is the need to supersede correlation to establish causality of potentially
pathogenic variants. This is complicated by the extensive nucleotide varia-
tion in the human genome, much of which is mysterious or, at best benign
polymorphism. Several things make this challenge more tractable. First, it is
very useful to be able to evaluate genomic sequences of patients in the con-
text of sequences of members, the nuclear family, especially parents or other
affected individuals. This allows for the elimination of variants that do not
track with disease, though one must be careful in eliminating potentially
causal variants in the case of incompletely penetrant disease. Second, it helps
to have sequences for unrelated individuals that have very closely matching
disease manifestations, especially those involving biochemical or molecular
similarities. Third, to possess an extended sequence database of individuals
from the proband’s race/ethnic background is beneficial, as the frequency
and identity of benign polymorphisms differ between ethnic populations.
The use of next-generation sequencing techniques and the increasing
deployment of whole-exome and whole-genome sequencing in the clinic
has greatly increased the amount of genetic information to compare against
and facilitated the identification of disease-associated variants. As investiga-
tors and clinicians look in to the future it will become increasingly necessary
to adopt whole-genome sequencing which is essential to identify noncoding
variants and provides better detection of exonic variants than whole-exome
sequencing (Belkadi et al., 2015). The tradeoff for the better sequence data is
the time and cost associated with whole-genome sequencing and the diffi-
culty inherent in analyzing noncoding variants—both problems that will
diminish with time.
Once a list of rare genetic variants that track with disease has been devel-
oped, there are usually multiple candidate variants remaining, especially
when only a single affected individual is available for analysis. Prioritization
of these candidate variants then occurs based on algorithms that predict a
deleterious effect on protein function (PolyPhen/CADD, etc.), the
observed vs expected mutation rates in the gene encoding the protein in
large-scale genetic databases such as ExAC, the tissue expression pattern
of the protein, the known or hypothetical roles of the protein, and the avail-
ability of genetic models in animals including mice, zebrafish, flies, etc. All of
this information is subjectively analyzed and variants are ranked for follow-
up analysis. Importantly, while coding variants (missense, nonsense, and
splice site) are perhaps the easiest to identify and study, noncoding variants
(promotor/enhancer/silencer mutations, copy number variation, intronic,
and synonymous) must also be considered as these can affect transcription,
translation, mRNA stability, or splicing of the affected gene, all with impacts
on protein function. Another interesting way to prioritize candidate genes is
the identification of genes likely to cause human disease based on their rela-
tionship with previously identified human PID genes. This approach has
shown good predictive capacity in identifying genes associated with yet-
undiscovered PIDs (Itan & Casanova, 2015).
Perhaps the easiest way to strengthen the argument that mutations in a
given gene are the cause of disease is the identification of multiple individuals
with a similar clinical phenotype with highly deleterious variants in the same
gene. Still, this does not move past correlation to implicate causation. To
move in this direction, additional laboratory testing must be done to estab-
lish that the given variant is deleterious to protein function and affects the
biological pathway that is presumed to be associated with disease. Usually
this first entails the identification of an in vitro cellular phenotype associated
with disease followed by add back of WT protein to patient cells or intro-
duction of patient protein/knockout of the gene in WT cells to determine if
these correct or phenocopy patient cellular defects, respectively. This can be
supplemented with pharmacological inhibition of the affected biochemical
pathway and the generation/use of genetically engineered animal models.
Casanova et al. have established three general guidelines that should be
viewed as prerequisites to identification and publication of causal genes in
cases involving a single affected individual (Itan & Casanova, 2015). First,
family and population genetics should indicate that the candidate genotype
is monogenic and the potential causal variant does not occur in healthy indi-
viduals. Second, experimental and mechanistic studies must prove that the
candidate variant is deleterious to the expression or function of the protein
product. Finally, the connection of the candidate gene and patient pheno-
type must be established by known molecular interactions, expression patterns,
and a relevant cellular or animal phenotype. Stated differently, the variant must
be proven deleterious and absent from healthy individuals and the gene the
variant resides in must be plausibly important for the disease mechanism. In
cases where a single patient has already been published, follow-up reports
are useful confirmations of gene–disease relationships and often provide insight
into the clinical spectrum of disease. Hence, although specific gene implication
will always involve a measure of correlation, if that can be established at the
molecular, cellular, and organismal levels, the hypothesis of causality is substan-
tially strengthened.
As mentioned throughout this review, identification of the causal variant
can lead to targeted therapeutic interventions. This has proven to be one of
the most exciting and gratifying aspects of genomic research. Those working
in the field of PID research and immunology is especially fortunate since
their “organ” of interest can be replaced through bone marrow transplanta-
tion. This enables a measure of manipulability that is unparalleled in other
organs in the body. The development of new treatments or the deployment
of known, but perhaps unobvious, treatments are facilitated by strong mech-
anistic evidence identifying the affected biochemical pathway in patient cells
and the availability of interventions that can target this pathway. In many
cases where disease is confined to the immune system and there is no known
targeted therapeutic option, HSCT is indicated as the principle course of
action. However, disease must be severe enough to warrant the inherent risk
associated with HSCT. More recently, the treatment of several PIDs
by genetic therapy based upon viral restitution of the gene/protein encoded
by the affected genetic loci, has been successful (Mukherjee & Thrasher,
2013). In the future, gene editing by CRISPR/Cas9 and similar technolo-
gies will likely play an important role in correcting these monogenic disor-
ders. Both gene therapy and genetic editing are made more attractive
in PIDs than other primary genetic disorders because it is possible to virtually
replace the all or part of the immune system with corrected material through
radioablation and replacement of patient bone marrow, or simple trans-
fer of corrected HSCs allowing for the outgrowth of corrected cells.
The likelihood of success of the latter approach is augured by the presence of

somatic reversion mutations in causative genes that correct the course of dis-
ease (Jing et al., 2014).
Future challenges facing researches studying PIDs include the need to
develop methods for predicting the impact of variants on the function of
intronic and other nonprotein-coding segments of the genome. Addition-
ally, we will begin to understand the clinical variability seen in PIDs (variable
expressivity and reduced penetrance) which likely occurs due to a conflu-
ence of Mendelian variant inheritance, infectious history, and alternate
genetic variants that may modify the clinical phenotype. Understanding this
matrix of factors that link genotype and phenotype will expedite the under-
standing and treatment of these diseases. Finally, as the field moves forward,
we will likely encounter more case reports where a given individual is
afflicted by more than one PID, with the clinical phenotype developing
in an additive fashion where the patient presents with the full spectrum of
symptoms from both PIDs, or a unique clinical spectrum arising from
two or more PIDs affecting overlapping pathways. In such cases, it will
be important to analyze patient mutations separately and in combination.
Finally, research will gradually divulge how the combination of two genes,
three genes, and, ultimately, polygenic constellations of variants will con-
tribute to the pathogenesis of a disease and its response to treatment. It seems
clear that the application of machine learning computational approaches will
be essential to derive the most knowledge from the expanding global corpus
of genomic DNA sequence data. Thus, although medicine and biomedical
research have reached a watershed moment in which human investigation
through the prism of genomics has greatly accelerated discovery, there is still
a vast terra incognita ahead for future generations of immunological and
genetic investigators.
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CHAPTER FOUR

Molecular Classification of Primary

Advances in Immunology, Volume 138 2018 Published by Elsevier Inc. 99

T lymphocyte cells (T cells) play a central role in the adaptive immune

to malignancy or infection), abnormal cellular homeostasis, autoimmunity,

variants in promoter or enhancer regions, that may alter the transcription of

3. PIDs OF T CELL FUNCTION

T cell function that are caused by alterations in antigen-presentation cells

3.1 Defects in T Cell Development

3.1.2 VDJ Recombination

in various proteins involved in the cutting, processing, and rejoining of

3.2 Mutations Affecting TCR Signaling

3.2.1 TCR Chains

tract infections, varicella and Epstein–Barr virus (EBV) infections, otitis

Sakaguchi, Appella, & Ashwell, 1994; Koretzky, Kohmetscher, & Ross,

macrophages, and CD3+ T cell as well as neutrophil necrosis. Additionally,

However, one patient also presented with bronchopulmonary disease and

3.2.8 Disorders of Phosphoinositide Signaling (PIK3CD, PIK3R1,

of related primary immune disorders (Lucas, Chandra, Nejentsev,

The PIK3R1 gene encodes several different regulatory subunits (p85α/

Interestingly, complete absence of p85α, due to a homozygous stop

3.2.9 ORAI-1 and STIM1 (Disorders of Ca2+ Flux)

result in either prolonged Ca2+ entry following stimulation or the sponta-

(SLAM)-associated protein (SAP). These variants were identified as the

production, chronic lymphadenopathy, and splenomegaly derived mainly

3.3 Defects in Costimulatory Pathways

3.3.1 CARMIL2/RLTPR Deficiency

infections, subcutaneous Staphylococcus, asthma associated with severe aller-

immunoglobulins, and attenuated germinal center formation (OMIM

3.3.4 CD40 Ligand (CD40LG/CD154)

hemophagocytosis, lymphoproliferation, hypogammaglobulinemia, and

3.4 Defects of Cytokine Signaling

3.4.1 CD132/Common Gamma Chain

antibody responses, athymia, reduced NK cell numbers, and absent

recessive disorder of growth hormone insensitivity, T cell lymphopenia, and

3.5 Defects in Adhesion, Migration, or Cytoskeletal

network while simultaneously protecting actin filaments from cofilin at the

3.5.9 Leukocyte Adhesion Deficiencies I (CD18) and III (Kindlin-3)

both lymphocytes and neutrophils is affected leading to severe bacterial

3.6 Defects in TFs/TF Regulation

lymphadenopathy, immunoglobulin deficiency, and respiratory tract infec-

3.6.4 NF-κB Family of TFs

mucocutaneous ulcerations, both due to increased TNF-induced epithe-

3.7 Defects in Apoptotic Pathways

3.7.1 Somatic Defects in Cytokine Withdrawal-Mediated Apoptosis

3.7.2 Death-Induced Signaling Complex Members

(Wang et al., 1999). LOF mutations in caspase 8 also impair FAS-induced

plays an important role in pattern recognition receptor signaling, which may

3.8 Defects in DNA Replication, Accessibility, Repair,

due to combined B and T cell defects including agammaglobulinemia,

3.8.2 DNA Ligase 1

ATM- and NBN-associated disease (OMIM 242900). SMARCAL1 is an

3.8.8 Defects in DNA Methylation (DNMT3B, ZBTB24, CDCA7,

a Tlow/NKlow/B+ CVID with reduced immunoglobulin levels and sus-

3.8.9 Defects in Telomere Maintenance (DKC1 and RTEL1)

T cell defects (Cossu et al., 2002). Defects in another protein involved in

3.9 Vesicular Trafficking and Protein Sorting

is essential for granule delivery to the IS and failures to coalesce at the

3.9.2 Lytic Granule Functional Deficiencies (Perforin-1, UNC13,

Some causal mutations in both Syntaxin-11 and Munc18-2 abrogate the

Tregs, B cell class switching, and plasmablast formation (Gamez-Diaz et al.,

required for Lck association and activation. In overexpression systems, and

3.10 Defects of Ubiquitination