Innate lymphoid cells

Jenny Mjsberg
Innate lymphoid cells (ILCs) are recently described
populations of lymphocytes that lack rearranged
antigen-specific receptors. The ILC family has been
divided into three main subsets ILC1, ILC2 and
ILC3 and also includes natural killer (NK) cells
and lymphoid tissue-inducer (LTi) cells. ILCs are
increasingly appreciated to have important immune
functions at mucosal surfaces, where they respond
to signals they receive from other cells in the tissue

Bone marrow
or fetal liver

NKP

EOMES,
IL-15,
T-bet

iILC1

ILC1

Activating IL-12,
IL-15,
factors
IL-18

IL-12,
IL-15

IL-12,
IL-18

IL-2, IL-25,
IL-33, PGD2,
TL1, TSLP

IL-2,
IL-12,
IL-18

IFN

AREG, GM-CSF,
IL-4, IL-5, IL-9,
IL-13

IFN

IFN, granzymes,
perforin

LTiP

TOX

BCL-11B,
GFI1, TCF1

NK
cell

Eector
molecules

ROR t,
RUNX3

AHR,
RORt,
RUNX3

BCL-11B,
GATA3, IL-2,
ILC2P Notch, ROR

RUNX3,
T-bet

Periphery

TCF1,
NFIL3, GATA3,
TOX
ID2,
IL-7
EILP
CHILP
PLZF
ILCP

EOMES,
T-bet

Skin

ILC development

CLP
EOMES,
ID2,
NFIL3

microenvironment. However, they can regulate

tissue homeostasis, inflammation and repair at
both mucosal and non-mucosal sites, including the
intestine, lungs and skin, as well as in adipose and
lymphoid tissues1. ILC effector functions are mainly
mediated through cytokine secretion and through
direct cellcell interactions with stromal cells and
other immune cells. This Poster summarizes some of
the key features of ILCs in homeostasis and disease.

NCR
ILC3

NCR
ILC3

LTi
cell

IL-1,
IL-2,
IL-6,
IL-23
GM-CSF,
IL-22, LT,
TNF

IL-1,
IL-2,
IL-6,
IL-23
GM-CSF,
IL-17,
LT

IL-1,
IL-2,
IL-23

exILC3

ILC2

IL-17,
IL-22,
LT, TNF

Much work has been done to define

the ontogeny of mouse ILCs; however,
human ILC development remains largely
uncharacterized. ILCs originate from a
common lymphoid progenitor (CLP),
which develops into either a common
helper innate lymphoid progenitor
(CHILP)2 under the influence of
transcription factors such as TCF13 and
ID2, or into an NK cell progenitor (NKP)4
under the additional influence of EOMES
and NFIL3. The subsequent expression
of RORt by the CHILP leads to LTi cell
differentiation via the LTi cell precursor
(LTiP), whereas PLZF expression marks
the development of the ILC progenitor
(ILCP) which, under the influence of
T-bet, GATA3 or RORt, gives rise to the
ILC1, ILC2 or ILC3 subsets, respectively5.
NCR+ ILC3s are characterized by IL-22
production, whereas NCR ILC3 produce
IL-17. Both subsets can differentiate
into IFN-producing exILC3s. The
development of intraepithelial ILC1s
(iILC1s) remains to be elucidated.

Homeostasis and Allergy

tissue repair
OVA, papain, HDM,
Bacteria Damage
calcipotriol or LPS

Homeostasis and
tissue repair

IL-22 produced by NCR+ ILC3s binds to the IL-22

receptor, which is exclusively expressed by nonhaematopoietic cells. The tissue protective role of
IL-22 in the intestine during intestinal infection has
been well documented10 and includes promotion
of epithelial cell fucosylation, which supports
hostmicrobiota symbiosis. However, the potent
capacity of IL-22 to induce proliferation of stromal
cells also implies that excessive IL-22 production
may lead to pathology. Indeed, in a mouse model
of colorectal cancer, tumour growth was enhanced
by ILC3-derived IL-2211. Intriguingly, whereas IL-22
seems mainly protective in the intestine, IL-22producing ILC3s accumulate in the skin of patients
with psoriasis12 and, supported by observations in
a mouse model of psoriasis13, this suggests a
disease-promoting role for these cells in this tissue.
Furthermore, in the lungs, ILC3s may promote
obesity-induced airway hyperresponsiveness
through the production of IL-17.

Virus

Airway hyperresponsiveness
and asthma
OVA, papain,
HDM or LPS

KLRG1
ILC2

IL-25,
IL-33, TSLP

Homeostatic
suppression of
ILC2 function

PGD2
Mast cell

ILC2

DC
IL-25,
IL-33,
TL1, TSLP

Airway remodelling
and neutrophil inux

LXA4
IL-4

ICOSL
ICOS

IgE isotype
B cell switch

IL-2

IL-9 IL-5

PGD2
Mast cell

ILC2 plasticity

IL-4,
IL-13

KLRG1hi

Inammatory
ILC2

IL-17RB

ILC3
IL-1

GM-CSF

LTD4
ILC2

Several mouse models and clinical observations support a role for

ILC2s in type 2 inflammation in the skin, lungs and intestine6,7,8. ILC2
activation is triggered by IL-25, IL-33, TSLP and PGD2 produced by
activated epithelial cells or immune cells in response to helminth
infections or allergen exposure. The effector functions of ILC2s are
largely mediated by IL-4, IL-5, IL-9 and IL-13 and promote goblet cell
hyperplasia, mucus production, eosinophilia, IgE isotype switching
and fibrosis1. Importantly, these mechanisms are mainly protective
in the setting of helminth infection, in which ILC2 responses are
driven predominantly by IL-33 but can become exaggerated and
cause pathology in allergy and asthma. Interestingly, ILC2s display
functional plasticity, and inflammatory ILC2s may also differentiate into
IL-17producing ILC3-like cells and participate in antifungal immunity9.

Candida
albicans

IL-25

TH2
cell

ILC2

DC

M1

NCR
ILC3

M2

IL-17
IL-13

Neutrophil

GM-CSF

ILC2s are involved in type 2 inflammation

Mucus
production

Fibrosis

IL-5

IL-17

IL-1,
IL-23

TH2
cell
IL-4,
IL-13

Eosinophilia

Goblet Goblet cell

cell
hyperplasia

AREG

IL-2

IL-22

NCR+
ILC3

IgE isotype
switch

IL-4

IL-9

ILC2

Obesity-induced airway
hyperresponsiveness

Basophil

B cell

IL-13

Keratinocyte
proliferation

IL-6,
IL-8,
CCL20

Fibrosis

DC

Repair
IL-33

Keratinocyte

Basophil

E-cadherin

Lung
The yin and yang of ILC3s

Psoriasis

Nippostrongylus IL-2,
IL-7,
brasiliensis
IL-33
low
KLRG1

M1
Macrophage

M2

IL-17

IL-13

IL-33
ST2

Eosinophilia

IL-5,
IL-13

ILC3like

Natural ILC2-like

High-fat diet

Adipose tissue
Intestine
Acute
infection

IBD

Homeostasis and
tissue repair
Mucus
layer

Intracellular
pathogen

Tumour

Helminth infection or
allergen exposure

Stem cell
regeneration
Epithelial
fucosylation

Neutrophil

Phagocytosis
and
cytotoxicity

Neutrophil
recruitment

IL-12,
IL-18

M1
Bacterial
killing

AREG
LT,
IL-22

ILC2

IL-6,
IL-23

IL-25,
IL-33,
TSLP

IL-9

IL-12,
IL-18

IFN

IL-5
TH2
cell

ILC3
IL-1,
IL-23,
retinoic
acid

M1
Tolerogenic
DC

Fibrosis

IL-2

IL-25
exILC3

ILC3

Mucus
production

IL-13

ILC2

IL-22BP
ILC1

MHC
Antigen
TCR
TH17
cell

Proliferation
and type 2
cytokine
production

IgE
B cell isotype
switch

ILC2

Beiging
White
adipocyte

Important tissue protective effects of ILC2s and ILC3s have been

described. ILC3s produce IL-22, which is crucial for the repair of
thymic tissue following viral infection14 and for intestinal mucosal
barrier protection10. In addition, ILC3s can suppress commensalspecific TH17 cells through IL-2 consumption, preventing intestinal
inflammation15. In the spleen, ILC3s interact with adaptive immune
cells to maintain memory CD4+ T cells16 and marginal zone (MZ)
Bcells17. Furthermore, ILC2s in adipose tissue produce metenkephalin (MetEnk), which promotes beiging of adipose tissue18.
Lung ILC2s contribute to tissue restoration upon viral insult
through the production of AREG19.

Eosinophil
Eosinophilia

Inhibition of
commensal-specic
TH17 cells through
IL-2 consumption

Stromal
cell

Tissue
restoration
after injury

IL-23

MADCAM1
47
integrin

DC
CD4+
T cell
CD30L
T cell memory CD30
maintenance

Abbreviations
AHR, aryl hydrocarbon receptor; AMPs, antimicrobial peptides; APRIL, a proliferation-inducing
ligand; AREG, amphiregulin; BAFF, B cell activating factor; BCL-11B, B cell lymphoma 11B;
CCL20, CC-chemokine ligand 20; CD30L, CD30 ligand; CD40L, CD40 ligand; DC, dendritic cell;
DLL1, delta-like protein 1; EILP, early ILC progenitor; EOMES, eomesodermin; GFI1, growth
factor independent protein 1; GM-CSF, granulocytemacrophage colony-stimulating factor;
HDM, house dust mite; ICAM1, intercellular adhesion molecule 1; ICOS, inducible T cell
costimulator; ICOSL, ICOS ligand; ID2, inhibitor of DNA binding 2; IFN , interferon- ;
IL, interleukin; IL-17RB, IL-17 receptor B; IL-22BP, IL-22 binding protein; KLRG1, killer-cell lectin like
receptor G1; LTD4, leukotriene D4; LPS, lipopolysaccharide; LT, lymphotoxin; LTR, lymphotoxin-
receptor; LXA4, lipoxin A4; M1, type 1 macrophage; M2, type 2 macrophage; MADCAM1, mucosal
addressin cell adhesion molecule 1; NCR, natural cytotoxicity receptor; NFIL3, nuclear factor IL-3
induced; OVA, ovalbumin; OX40L, OX40 ligand; PGD2, prostaglandin D2; PLZF, promyelocytic
leukaemia zinc finger protein; ROR, retinoic acid receptor-related orphan receptor; RUNX3,
runt-related transcription factor 3; ST2, IL-33 receptor; TCF1, T cell factor 1; TCR, T cell receptor;
TH, T helper; TL1, TNF-like ligand 1; TNF, tumor necrosis factor; TSLP, thymic stromal lymphopoietin;
VCAM1, vascular cell adhesion molecule 1; VIP, vasoactive intestinal peptide.
2015 Macmillan Publishers Limited. All rights reserved

MSC

IL-22,
LT

Human inflammatory bowel disease (IBD) is associated with an increased frequency of IL-17-producing ILC3s20, which parallels findings in mice, in which
Helicobacter hepaticus-induced colitis increases the number of IL-17- and IFN-producing ILC3s21. Noteworthy, neutralization of IL-17 in this model, or in
clinical trials, does not ameliorate disease, pointing towards a crucial role for ILC3-derived IFN in IBD. In mice, intestinal environmental cues induce
T-bet expression in RORt+NCR+ ILC3s, which is crucial for defence against Salmonella infection22. However, this causes collateral damage that presents
as enterocolitis. Paralleling these observations, human Crohn's disease is associated with an accumulation of IFN-producing ILC1s23. ILC1s can be
derived from ILC3s under the influence of IL-12, whereas IL-23 and retinoic acid exposure lead to ILC3 re-differentiation24. Hence, a finely tuned balance
of ILC1s and ILC3s ensures tissue integrity while maintaining immune defence in the intestine.

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Document # 27005 Version 1.0.0

IL-13,
MetEnk

Spleen and thymus

ILCs contribute to intestinal inflammation and are functionally plastic

STEMCELL Technologies

Metabolic
homeostasis

The role for ILCs in homeostasis and tissue repair

Mucins,
AMPs,
proliferation

IL-17

ILC1
IFN

IFN

iILC1

IL-33

IL-25,
IL-33,
VIP

Intestinal
epithelial
cell

Goblet
cell

Repair
DC

Beige
adipocyte

Source?

CD4+
T cell

ICAM1
VCAM1

LT,
TNF
CD40L
CD40
MZ
ILC3
B cell
DLL1
OX40L
OX40

BAFF

GM-CSF

Survival
Proliferation
IgM, IgA and
IgG production
Plasmablast
dierentiation
APRIL
Neutrophil

Affiliations
Jenny Mjsberg is at the Center for Infectious Medicine, Department
of Medicine Huddinge, Karolinska University Hospital Huddinge,
Karolinska Institutet, S-14186 Stockholm, Sweden.
(jenny.mjosberg@ki.se)
The author apologizes to colleagues whose work has not been cited
owing to space limitations.
References and a table of the surface markers expressed by human
and mouse ILCs are available online.
Edited by Olive Leavy and Jamie D. K. Wilson; copy-edited by
Gemma Ryan; designed by Kirsten Lee and Simon Bradbrook.
2015 Nature Publishing Group. All rights reserved.
www.nature.com/posters/ilcs/index.html