How NK cells influence disease

Loris Zamai
Department of human, environmental and natural Sciences; Cytometry and Cytomorphology Center, University of Urbino; INFN LNGS Assergi, LAquila

Natural Killer Cells

Site of generation: Bone marrow (lymph nodes ...) Morphology: Large granular lymphocytes Phenotype: CD56+, CD16+, CD161+, IL-2R, TCR-, sIg-;
Inhibitory receptors : KIR+, CD94/NKG2A; Activatory receptors: NCRs, NKG2D, 2B4 Function: 1. Cytotoxic activity mediated by lytic protein
(perforin and granzymes) secretion or by surface molecules (FasL and TRAIL) without prior sensitization (vs. tumor and virus-infected cells)

2. Cytokine secretion (IFN- , TNF-, GM-CSF, IL-5 etc.)

Cytotoxic activity and cytokine production

Granule exocytosis (Ca2+-dependent) Perforin Granzymes

Target: Cytostasis Differentiation Death

Target: Necrosis Apoptosis

Cytokine secretion TNF- GM-CSF IFN- IL-5

TRAIL (inducible)/TRAIL-Rs Fas-L (inducible) /Fas (Ca2+-independent)

Similar to CD8 and CD4 T cells, NK cells can be divided in two different subsets
CD56dim cells are highly cytotoxic preferentially express KIRs and CD16 (that mediate antiboby dependent cell cytotoxicity, ADCC) and are preferentially activated after target cell recognition CD56bright cells produce high amounts of cytokines and preferentially express CD94-NKG2A inhibitory receptors and CD117 (c-kit), CD25 (IL-2 receptor alfa chain), CD62L, CCR7 (lymph node homing receptor) and are preferentially activated via cytokines (DCderived IL-15, IL-12 and T cell-derived IL-2)

Peripheral blood NK cell subsets

CD56dim 95% of PB NK cells More mature?

highly cytotoxic

Peripheral blood NK cell subsets

CD56bright 5% of PB NK cells, are present in the lymph nodes more immature?

NK and LAK (lymphokine activated killer) NK Cell Functions cells can kill via different mechanisms

NK cell functions are regulated by activatory and inhibitory receptors (NKR)

NCRs,NKG 2D NKR

NK cells express a lot NK different activating receptors

Moretta L and A, EMBO,2004, 23, 255

Other activating receptors on human NK cells engaged by their ligands on targets

Activation via ITAM induces Vav1 phosphorilation

A lot of different inhibitory receptors are expressed by human NK cells

ITIM recruit a phosphatase, SHP-1, that dephosphorilates Vav1, blocking all activatory pathways

Bryceson et al. (2006) Immunol. Rev.

receptors (lectin-like and immunoglobulin-like) expressed on subsets of NK Heterodimeric Killer Ig-like cells receptor receptors
CD94/NKG2A,B
There are also activating version CD94/NKG2C and E

(KIRs) with 2 or 3 Ig-like domains KIR2DL and also There are KIR3DL activating version
KIR2DS and KIR3DS with a short intracytoplasmic tail

CD158 CD158e

HLA class I-specific inhibitory receptors on human NK cells (KIR, CD94/NKG2A) binds to different HLA oligomorphic epitopes

CD158b CD158a CD158e

Recruitment of SHP-1 phosphatase via ITIM induces Vav1

Activatory signals from activating receptors are blocked by HLA class I inhibitory receptors engaged by self HLA molecules

Missing self recognition

Missing self recognition of NK cells can occur in haploidentical hematopoietic stem cell transplantation

Velardi et al. 2008

Selection of donor NK cells with donor versus recipient alloreactivity improves haploidentical hematopoietic stem cell transplantation

Moretta et al. 2009

Selection of donor NK cells with donor versus recipient alloreactivity : involvement of activating KIR (KIR2DS1)

Complementary role of T and NK cells in MHC-driven cell cytotoxicity: self-MHC-I inhibits (NK), activates (T)
NKG2D ULBPs MICA/B NCR KIR MHC-I CD94/NKG2A

TCR-1 MHC-I

NO LYSIS
CD94/NKG2A KIR NCR ULBPs NKG2D MICA/B

LYSIS
TCR-1

LYSIS

NO LYSIS

NK cells act early during immune response before the activation of CTLs responsible for virus eradication

Evidence of long lasting control of some diseases performed by NK cells depending on KIRs/HLA-I pairs
Some KIRs/HLA-I pairs protect from: 1) virus progression 2) tumor progression Finally some KIRs-HLA-I pairs predispose to autoimmunity

killer immunoglobulin-like receptors KIRs

recognize oligomorphic regions of HLA-I molecule (KIR-ligand). evolutively recent molecules (mice do not expressed KIRs but lectin-like, Ly49 molecules with similar function but different structure) probably specialized to fight new evolved diseases (i.e. HIV)

Evidences that some KIR/HLA-I pairs give protection against virus

Cytomegalovirus (CMV) Human immunodeficiency virus (HIV) Hepatitis C virus (HCV)

First evidence that NK cells protects from virus (CMV) progression in mice

Similar to CMV in mouse, an activatory KIR give protection from AIDS progression in humans

Some KIR/HLA-I pairs protect from AIDS progression

Some KIR/HLA-I pairs protect from HIV replication in vitro

Some KIR/HLA-I pairs (KIR2DL3/HLAC1) protect from HCV progression

Intriguingly, KIR2DL3 has a low affinity for its ligand, HLA-C1

And NK cells can recognize peptides on HLA-C1

a possibility of a masking self recognition when a viral peptide is mounted on HLA-I, in particular in KIR/HLA-I pairs with low affinity binding (KIR2DL3/HLA-C1)

Evidences that some KIR/HLA-I pairs give protection against tumor progression Cervical neoplasia Melanoma Leukaemia

Some KIR-HLA-I pairs give protection from cervical neoplasia

Some KIR-HLA-I pairs give protection from malignant melanoma

Expansion of some NK (CD158a+) cells from melanoma patients expressing the corresponding HLA-C ligand, suggests their involvement in the control of the disease

Some KIRs predispose to leukaemia development

May some other KIRs protect from leukaemia?

NK cells and predisposition to autoimmune diseases Psoriatic Arthritis Ankylosing Spondylitis Diabetes Multiple sclerosis

Some KIR/HLA-I pairs predispose to psoriatic arthritis

Some KIR-HLA-I pairs predispose to ankylosing spondylitis

Some KIR/HLA-I pairs predispose to diabetes

Some KIR/HLA-I pairs predispose to severe Multiple sclerosis

Similar to T, NK cells can be activated by DC

Moreover . NK cells with Memory function

Memory NK cells

Finally, NK cells as effectors of vaccine-induced immunity

Conclusions: in some cases NK cells seems to do a job similar to CTLs

Depending on: 1) the disease (relatively new pathogens); 2) the HLA-I (KIR ligand and/or TcR ligand) and 3) the KIRs expressed by the subjects it can be predisposed a NK cell: 1) immunosurveillance of viral-infected or cancer cells 2) autoimmune response

A possible complementary role of T and NK cells within the human population