Innate lymphoid cells

Jenny Mjsberg
Innate lymphoid cells (ILCs) are recently described microenvironment. However, they can regulate
populations of lymphocytes that lack rearranged tissue homeostasis, inflammation and repair at
antigen-specific receptors. The ILC family has been both mucosal and non-mucosal sites, including the
divided into three main subsets ILC1, ILC2 and intestine, lungs and skin, as well as in adipose and
ILC3 and also includes natural killer (NK) cells lymphoid tissues1. ILC effector functions are mainly
and lymphoid tissue-inducer (LTi) cells. ILCs are mediated through cytokine secretion and through
increasingly appreciated to have important immune direct cellcell interactions with stromal cells and
functions at mucosal surfaces, where they respond other immune cells. This Poster summarizes some of
to signals they receive from other cells in the tissue the key features of ILCs in homeostasis and disease.

Bone marrow ILC development Skin

or fetal liver CLP Much work has been done to define Homeostasis and Allergy Psoriasis
the ontogeny of mouse ILCs; however, tissue repair
TCF1, OVA, papain, HDM,
EOMES, NFIL3, GATA3, human ILC development remains largely Bacteria Damage calcipotriol or LPS
ID2, TOX ID2, uncharacterized. ILCs originate from a Keratinocyte
NFIL3 IL-7
EILP common lymphoid progenitor (CLP),
NKP CHILP ROR t, which develops into either a common
PLZF RUNX3 helper innate lymphoid progenitor
(CHILP)2 under the influence of E-cadherin Basophil
Fibrosis IL-6, Keratinocyte
? ILCP LTiP transcription factors such as TCF13 and KLRG1 IL-8, proliferation
EOMES, AHR, IL-13 B cell
IL-15, EOMES, ID2, or into an NK cell progenitor (NKP)4 DC CCL20
T-bet RORt, IL-22
T-bet BCL-11B, RUNX3 under the additional influence of EOMES ILC2
IL-4 IgE isotype NCR+
GATA3, IL-2, IL-9 ILC3
and NFIL3. The subsequent expression IL-25, switch IL-17
TOX IL-2
ILC2P Notch, ROR of RORt by the CHILP leads to LTi cell Homeostatic IL-33, TSLP
suppression of TH2 IL-1,
RUNX3, differentiation via the LTi cell precursor ILC2 function ILC2 IL-23
T-bet BCL-11B, cell
Periphery GFI1, TCF1 (LTiP), whereas PLZF expression marks
PGD2
the development of the ILC progenitor GM-CSF Neutrophil
Mast cell IL-4,
NK NCR +
NCR
LTi (ILCP) which, under the influence of IL-5 IL-13 DC NCR
iILC1 ILC1 ILC2 exILC3 ILC3 ILC3 cell ILC3
cell T-bet, GATA3 or RORt, gives rise to the M1
Activating IL-12, IL-12, IL-12, IL-2, IL-25, IL-2, IL-1, IL-1, IL-1, ILC1, ILC2 or ILC3 subsets, respectively5. Eosinophilia M2
factors IL-15, IL-15 IL-18 IL-33, PGD2, IL-12, IL-2, IL-2, IL-2, NCR+ ILC3s are characterized by IL-22
IL-18 TL1, TSLP IL-18 IL-6, IL-6, IL-23 production, whereas NCR ILC3 produce
IL-23 IL-23
IL-17. Both subsets can differentiate
Eector IFN, granzymes, IFN AREG, GM-CSF, IFN GM-CSF, GM-CSF, IL-17, into IFN-producing exILC3s. The
ILC2s are involved in type 2 inflammation
molecules perforin IL-4, IL-5, IL-9, IL-22, LT, IL-17, IL-22, Several mouse models and clinical observations support a role for
IL-13 TNF LT LT, TNF development of intraepithelial ILC1s
(iILC1s) remains to be elucidated. 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
Lung largely mediated by IL-4, IL-5, IL-9 and IL-13 and promote goblet cell
The yin and yang of ILC3s Homeostasis and
tissue repair
Airway hyperresponsiveness
and asthma
Obesity-induced airway
hyperresponsiveness
hyperplasia, mucus production, eosinophilia, IgE isotype switching
and fibrosis1. Importantly, these mechanisms are mainly protective
IL-22 produced by NCR+ ILC3s binds to the IL-22 OVA, papain,
Virus Goblet Goblet cell in the setting of helminth infection, in which ILC2 responses are
receptor, which is exclusively expressed by non- HDM or LPS
cell hyperplasia driven predominantly by IL-33 but can become exaggerated and
haematopoietic cells. The tissue protective role of
cause pathology in allergy and asthma. Interestingly, ILC2s display
IL-22 in the intestine during intestinal infection has
Repair functional plasticity, and inflammatory ILC2s may also differentiate into
been well documented10 and includes promotion
Basophil IL-17producing ILC3-like cells and participate in antifungal immunity9.
of epithelial cell fucosylation, which supports Fibrosis Mucus Airway remodelling
IL-33 AREG and neutrophil inux
hostmicrobiota symbiosis. However, the potent production
capacity of IL-22 to induce proliferation of stromal LXA4
ILC2 plasticity
cells also implies that excessive IL-22 production ILC2 DC IL-17
IL-13 KLRG1hi Inammatory
may lead to pathology. Indeed, in a mouse model IL-4 IgE isotype
IL-25, B cell switch ILC2
of colorectal cancer, tumour growth was enhanced IL-33, ICOSL IL-2 ILC3 IL-17RB ILC3-
TL1, TSLP ICOS Candida like
by ILC3-derived IL-2211. Intriguingly, whereas IL-22 TH2 IL-25
ILC2 albicans
seems mainly protective in the intestine, IL-22- cell
IL-1 Nippostrongylus IL-2,
producing ILC3s accumulate in the skin of patients LTD4 GM-CSF brasiliensis IL-7,
with psoriasis12 and, supported by observations in IL-33 IL-5, IL-17
a mouse model of psoriasis13, this suggests a ILC2 KLRG1 low IL-13
IL-9 IL-5 IL-4, M1
disease-promoting role for these cells in this tissue. IL-13 Macrophage IL-33 IL-13
Furthermore, in the lungs, ILC3s may promote PGD2 M2
ST2 Natural ILC2-like
obesity-induced airway hyperresponsiveness
through the production of IL-17.
Mast cell Eosinophilia High-fat diet

Adipose tissue
Intestine Source? Beige
adipocyte Metabolic
homeostasis
Acute IBD Homeostasis and Tumour Helminth infection or IL-25,
infection tissue repair allergen exposure IL-33, IL-13,
Intestinal VIP MetEnk
Mucus Beiging
Intracellular layer Goblet epithelial ILC2
pathogen Stem cell cell cell
regeneration
Epithelial White
fucosylation The role for ILCs in homeostasis and tissue repair adipocyte
Repair Important tissue protective effects of ILC2s and ILC3s have been
Neutrophil Phagocytosis Mucins, IL-25, Mucus described. ILC3s produce IL-22, which is crucial for the repair of
and IL-33 AREG AMPs, IL-33, production
DC Neutrophil IL-9 TSLP
thymic tissue following viral infection14 and for intestinal mucosal
cytotoxicity proliferation
recruitment LT, barrier protection10. In addition, ILC3s can suppress commensal-
iILC1 IFN ILC2 IL-22 specific TH17 cells through IL-2 consumption, preventing intestinal
IL-12, IL-13
ILC2 Fibrosis inflammation15. In the spleen, ILC3s interact with adaptive immune
IL-18 IL-17 IL-22BP
IL-2
cells to maintain memory CD4+ T cells16 and marginal zone (MZ)
ILC1 IL-25 Bcells17. Furthermore, ILC2s in adipose tissue produce met-
ILC1 IL-5 IgE
B cell isotype enkephalin (MetEnk), which promotes beiging of adipose tissue18.
TH2 switch Lung ILC2s contribute to tissue restoration upon viral insult
ILC3 exILC3 ILC3
IFN IL-6, cell
IL-23 IL-1, through the production of AREG19.
MHC
IL-23, Proliferation
IL-12,
IL-18 retinoic
Antigen
TCR
and type 2 Spleen and thymus
M1 IFN acid cytokine
TH17 production Eosinophil Tissue
cell Stromal restoration
Bacterial M1 Eosinophilia after injury
killing cell ICAM1
Inhibition of MSC VCAM1
commensal-specic IL-22,
Tolerogenic TH17 cells through MADCAM1
DC LT LT, Survival
IL-2 consumption 47 Proliferation
IL-23 TNF
integrin IgM, IgA and
CD40L
ILCs contribute to intestinal inflammation and are functionally plastic DC CD40 IgG production
MZ Plasmablast
Human inflammatory bowel disease (IBD) is associated with an increased frequency of IL-17-producing ILC3s20, which parallels findings in mice, in which CD4+
ILC3 B cell dierentiation
T cell DLL1
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 CD30L APRIL
T-bet expression in RORt+NCR+ ILC3s, which is crucial for defence against Salmonella infection22. However, this causes collateral damage that presents T cell memory CD30 OX40L BAFF
maintenance OX40
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 CD4+ Neutrophil
T cell GM-CSF
of ILC1s and ILC3s ensures tissue integrity while maintaining immune defence in the intestine.

STEMCELL Technologies RoboSep (www.RoboSep.com), the fully Abbreviations Affiliations

STEMCELL Technologies offers a complete portfolio of AHR, aryl hydrocarbon receptor; AMPs, antimicrobial peptides; APRIL, a proliferation-inducing Jenny Mjsberg is at the Center for Infectious Medicine, Department
automated cell isolation platform, performs all
ligand; AREG, amphiregulin; BAFF, B cell activating factor; BCL-11B, B cell lymphoma 11B; of Medicine Huddinge, Karolinska University Hospital Huddinge,
fast and easy cell isolation products, including solutions cell labeling and magnetic isolation steps using CCL20, CC-chemokine ligand 20; CD30L, CD30 ligand; CD40L, CD40 ligand; DC, dendritic cell;
for the isolation of ILCs. Our wide range of positive and EasySep reagents to reduce hands-on time and Karolinska Institutet, S-14186 Stockholm, Sweden.
DLL1, delta-like protein 1; EILP, early ILC progenitor; EOMES, eomesodermin; GFI1, growth (jenny.mjosberg@ki.se)
negative cell isolation kits are proven to rapidly give increase laboratory throughput. factor independent protein 1; GM-CSF, granulocytemacrophage colony-stimulating factor;
you high recovery and purity of functional cells from RosetteSepTM (www.RosetteSep.com) is a unique HDM, house dust mite; ICAM1, intercellular adhesion molecule 1; ICOS, inducible T cell The author apologizes to colleagues whose work has not been cited
virtually any sample source including fresh and immunodensity cell isolation system for the isolation costimulator; ICOSL, ICOS ligand; ID2, inhibitor of DNA binding 2; IFN , interferon- ; owing to space limitations.
previously frozen peripheral blood mononuclear cells of untouched cells directly from whole blood during IL, interleukin; IL-17RB, IL-17 receptor B; IL-22BP, IL-22 binding protein; KLRG1, killer-cell lectin like References and a table of the surface markers expressed by human
(PBMCs), Leuko Paks, whole blood, bone marrow, the standard density centrifugation step. receptor G1; LTD4, leukotriene D4; LPS, lipopolysaccharide; LT, lymphotoxin; LTR, lymphotoxin- and mouse ILCs are available online.
lymph nodes, and spleen. For more information on the complete range of cell 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 Edited by Olive Leavy and Jamie D. K. Wilson; copy-edited by
EasySep (www.EasySep.com) is a fast, easy and separation products available, or to learn more about induced; OVA, ovalbumin; OX40L, OX40 ligand; PGD2, prostaglandin D2; PLZF, promyelocytic Gemma Ryan; designed by Kirsten Lee and Simon Bradbrook.
column-free immunomagnetic cell separation system primary cells, cell culture media, antibodies or other leukaemia zinc finger protein; ROR, retinoic acid receptor-related orphan receptor; RUNX3,
for isolating highly purified immune cells in as little products for your immune cell workflow, please visit runt-related transcription factor 3; ST2, IL-33 receptor; TCF1, T cell factor 1; TCR, T cell receptor;
as 8minutes. Cells are immediately ready for our website: www.stemcell.com TH, T helper; TL1, TNF-like ligand 1; TNF, tumor necrosis factor; TSLP, thymic stromal lymphopoietin; 2015 Nature Publishing Group. All rights reserved.
downstream functional assays. Document # 27005 Version 1.0.0 VCAM1, vascular cell adhesion molecule 1; VIP, vasoactive intestinal peptide. www.nature.com/posters/ilcs/index.html

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