Leading Edge

Review

Innate Lymphoid Cells: 10 Years On

Eric Vivier,1,2,* David Artis,3 Marco Colonna,4 Andreas Diefenbach,5,6,7 James P. Di Santo,8,9 Gérard Eberl,10,11
Shigeo Koyasu,12,13 Richard M. Locksley,14 Andrew N.J. McKenzie,15 Reina E. Mebius,16 Fiona Powrie,17
and Hergen Spits18
1Innate Pharma Research Labs, Innate Pharma, Marseille, France
2Aix Marseille University, CNRS, INSERM, APHM, CIML, Hôpital de la Timone, Immunologie, Marseille-Immunopole, Marseille, France
3Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine and Department of

Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
4Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
5Laboratory of Innate Immunity, Department of Microbiology and Infection Immunology, Charité – Universitätsmedizin, Berlin, Germany
6Berlin Institute of Health, Berlin, Germany
7Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, Berlin, Germany
8Innate Immunity Unit, Institut Pasteur, Paris, France
9Inserm U1223, Paris, France
10Microenvironment & Immunity Unit, Institut Pasteur, Paris, France
11INSERM U1224, Paris, France
12Laboratory for Immune Cell Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
13Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
14HHMI and Department of Medicine, University of California San Francisco, San Francisco, CA, USA
15Medical Research Council Laboratory of Molecular Biology, Cambridge, UK
16Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
17Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
18Department of Experimental Immunology Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands

*Correspondence: vivier@ciml.univ-mrs.fr
https://doi.org/10.1016/j.cell.2018.07.017

Innate lymphoid cells (ILCs) are lymphocytes that do not express the type of diversified antigen
receptors expressed on T cells and B cells. ILCs are largely tissue-resident cells and are deeply
integrated into the fabric of tissues. The discovery and investigation of ILCs over the past decade
has changed our perception of immune regulation and how the immune system contributes to the
maintenance of tissue homeostasis. We now know that cytokine-producing ILCs contribute to mul-
tiple immune pathways by, for example, sustaining appropriate immune responses to commensals
and pathogens at mucosal barriers, potentiating adaptive immunity, and regulating tissue inflam-
mation. Critically, the biology of ILCs also extends beyond classical immunology to metabolic
homeostasis, tissue remodeling, and dialog with the nervous system. The last 10 years have also
contributed to our greater understanding of the transcriptional networks that regulate lymphocyte
commitment and delineation. This, in conjunction with the recent advances in our understanding of
the influence of local tissue microenvironments on the plasticity and function of ILCs, has led to a
re-evaluation of their existing categorization. In this review, we distill the advances in ILC biology
over the past decade to refine the nomenclature of ILCs and highlight the importance of ILCs in
tissue homeostasis, morphogenesis, metabolism, repair, and regeneration.

Innate lymphoid cells (ILCs), which lack adaptive antigen recep-
tors generated by the recombination of genetic elements, are the
innate counterparts of T lymphocytes (Spits et al., 2013; Eberl
et al., 2015; Artis and Spits, 2015). ILC1s, ILC2s, and ILC3s mirror
CD4+ T helper (Th)1, Th2, and Th17 cells, respectively, in terms of
function, whereas natural killer (NK) cells mirror the functions of
CD8+ cytotoxic T cells. ILCs and T cells play key roles in orches-
trating the most appropriate immune response to the threat faced
by the individual. ILC1s and Th1 cells react to intracellular patho-
gens, such as viruses, and to tumors; ILC2s and Th2 cells
respond to large extracellular parasites and allergens; and
ILC3s and Th17 cells combat extracellular microbes, such as
bacteria and fungi. Myeloid and non-hematopoietic cells instruct
the ILCs and T cells, which belong to the lymphoid lineage, about
the type of threat they will confront. The ILCs and T cells react by
providing positive and negative feedbacks and through immune
regulatory and effector functions. This initial description of a
simple phenotypic and functional trichotomy has been greatly
enriched and has become much more complex since the discov-
ery of these subsets 10 years ago. This review aims to clarify this
complexity and to propose an updated and operational classifi-
cation and nomenclature for ILCs.
ILCs act early in the immune response by reacting promptly to
signals, or inducer cytokines, expressed by tissue-resident cells.

1054 Cell 174, August 23, 2018 ª 2018 Elsevier Inc.

By contrast, the T cell response takes several days, as these
cells must undergo clonal expansion to become operational
and develop antigen-specific memory. Nevertheless, several
types of T cells are ‘‘pre-programmed’’ and function like innate
cells in certain tissues. These cells include invariant NKT cells,
mucosa-associated invariant T (MAIT) cells, diverse subsets of
gd T cells and resident memory T (TRM) cells selected and
expanded during earlier encounters with antigen (Mueller and
Mackay, 2016). A few days after the initiation of an immune reac-
tion, both ILCs and T cells are active, and they cross-regulate
each other. ILCs can express major histocompatibility complex
(MHC) class II molecules and process antigens, thereby regu-
lating the activity of antigen-specific T cells (Oliphant et al.,
2014). In turn, these T cells produce interleukin-2 (IL-2), promot-
ing ILC activities. Both types of cell generate positive-feedback
loops that amplify their responses, but they also compete for
the same inducer cytokines and survival factors. Thus, these
two types of lymphoid cells mirror one another’s activities only
partially, thereby ensuring the timely orchestration of the immune
response.
ILCs begin functioning during fetal development, as lymphoid
tissue-inducer cells (LTi cells) (Mebius et al., 1997). These cells
induce the development of most of the secondary lymphoid or-
gans. They instruct mesenchymal stromal cells to produce the
factors required to attract hematopoietic cells to the developing
lymphoid structure and retain them there. The interaction between
ILCs and the non-hematopoietic microenvironment is an impor-
tant facet of ILC function maintained from birth into adulthood. It
includes the activation of stromal cells for the recruitment, reten-
tion, and activation of lymphocytes, and for their regeneration
and the activation of defensive and anti-apoptotic programs in
epithelial cells. Thus, through their generation early during the for-
mation of the immune system and their prompt reactivity, ILCs play
an important role in the crosstalk of lymphoid cells with non-he-
matopoietic cells and in the spatial organization of immunity.
ILCs are clearly the innate counterpart of T cell effector sub-
sets, but research into ILCs has opened up an unprecedented
appreciation of the profound involvement of immune cells in tis-
sue homeostasis, whether morphogenesis, metabolism, regen-
eration, and growth. ILCs are largely tissue-resident cells and
are integrated deep into the fabric of tissues, and studies of
these cells have revealed ever more intriguing relationships
with basic developmental and biological processes. ILCs play
a key role in homeostasis, due to the rapidity with which they
react and their presence in normal healthy tissues, including
the intestine, lung and adipose tissues, in particular. An absence
of ILC3s in the intestine can lead to a loss of control over the
symbiotic microbiota. In adipose tissues, ILC2s are involved in
thermogenesis in the context of a cold shock. ILCs are also
involved in tissue tolerance and regeneration in response to
tissue damage. In the intestine and thymus, ILC3s mediate toler-
ance to chemical toxins and irradiation through the activation of
epithelial cells, whereas ILC2s produce amphiregulin (AREG),
a member of the EGF family, which is involved in epithelial
cell regulation. However, these functions can also favor the
development of carcinoma during chronic inflammation and
injury, and increase the severity of inflammation induced by
pathogens.
The presence of ILCs in non-lymphoid tissues is ensured by
the recruitment of ILC progenitors from the blood, and main-
tained by the expression of local survival factors, such as IL-7.
ILCs have slightly different phenotypes in different tissues, and
different local microenvironments may induce ILC progenitors
from the same subset to adopt tissue-specific expression pat-
terns. Most ILCs are tissue-resident cells (Gasteiger et al.,
2015), but ILC3s can migrate from the intestinal lamina propria
to the draining mesenteric lymph node, and NK cells and inflam-
matory ILC2s circulate in the bloodstream.
We first proposed a common nomenclature for ILCs and ILC
subsets in 2013 (Spits et al., 2013). The use of single-cell RNA
sequencing has led to the identification of more than 50 distinct
ILC clusters (in t-distributed stochastic neighbor embedding
[t-SNE] projection analysis) in different tissues (Gury-BenAri
et al., 2016). We have re-evaluated the original nomenclature,
taking into account the identification of ILC developmental
lineages, transcriptional networks coordinating ILC effector func-
tions and phenotypes, activation states, and tissue-specific ad-
aptations, and we propose here an updated and comprehensive,
but simple and practical, nomenclature for ILCs. We also provide
an overview of the newly discovered roles of ILCs in defense,
metabolism, repair and interactions with the nervous system.
Nomenclature
The nomenclature for ILCs proposed in 2013 classified these
cells into groups 1, 2, and 3, each of which contained one, two
or three subsets. The subsets within each group had the same
output, including cytokines in particular, and their development
and function were dependent on the same transcription factors.
Group 1 ILCs comprised NK cells and ILC1s. These cells are
dependent on the T-box transcription factor Tbet for their devel-
opment and function, and they produce interferon-gamma
(IFN-g). Group 2 contains a single subset, ILC2s, which are
dependent on GATA3 and RORa (Wong et al., 2012), and pro-
duce type 2 cytokines, predominantly IL-5 and IL-13. Group 3
ILCs include natural cytotoxicity receptor (NCR) ILC3s, NCR+
ILC3s, and LTi cells, all of which are dependent on the transcrip-
tion factor RORgt and can produce IL-17 and/or IL-22.
The last decade has provided a wealth of data on the mecha-
nisms of development and the molecules involved in the
functions of T helper cell subsets, which has improved our un-
derstanding of the development of ILC subsets (Eberl et al.,
2015; Artis and Spits, 2015). Within the three initially proposed
ILC groups, we now appreciate the existence of distinct subsets
based on developmental trajectories. As such, we now propose
to classify ILCs into five subsets—NK cells, ILC1s, ILC2s, ILC3s,
and LTi cells—based on their development (Figure 1) and func-
tion (Figure 2). The ILC nomenclature presented here is approved
by the International Union of Immunological Societies (IUIS).
NK Cells and ILC1s
NK cells are dedicated cytotoxic cells that circulate in the blood-
stream (Vivier et al., 2011). They can kill virus-infected normal
and tumor cells. In the mouse thymus, conventional NK cells
(cNK) coexist with ILC1s that express CD127 (IL-7Ra) and
GATA3, unlike cNK cells, produce IFN-g and granulocyte-
macrophage colony-stimulating factor (GM-CSF) at much higher
levels than cNK cells, and depend on the cytokine IL-7 and the
Cell 174, August 23, 2018 1055

transcription factor GATA3 for their differentiation (Vosshenrich
et al., 2006). ILC1s are generally non-cytotoxic or weakly cyto-
toxic and function as a first line of defense against infections
with viruses and certain bacteria, such as T. gondii (Klose
et al., 2014) or C. difficile (Abt et al., 2015). NK cells and ILC1s
have several features in common. Both these cell types produce
IFN-g as their principal cytokine output and require Tbet for this
function. However, they have different developmental paths
(Figure 1). In both humans and in mice, NK cells develop from
a common innate lymphoid progenitor (CILP) via an NK cell pre-
cursor (NKP), whereas ILC1s develop from CILPs via an innate
lymphoid cell precursor (ILCP) (Constantinides et al., 2014; Klose
et al., 2014; Lim et al., 2017; Renoux et al., 2015; Scoville et al.,
2016). NK cells and ILC1s are functionally different, as NK cells
are dedicated cytotoxic cells strongly expressing perforin,
whereas ILC1s have low levels of perforin expression. However,
regardless of these developmental and functional differences,
the phenotypic characterization of ILC1s is often problematic.
ILC1s preferentially express CD49a and TRAIL in both humans
and mice, but the specificity of these markers is often lost
upon cell activation and is tissue-dependent. ILC1s have some
phenotypic markers in common with NK cells and ILC3s, in at
least some organs. These markers include NK1.1 in mice, and
NCRs, such as NKp44 in humans, and NKp46 in both humans
and mice (Table 1). In humans, ILC1s express CD127 whereas
highly cytotoxic CD16+CD56+ NK cells do not express this
marker. However, CD127 may not be an absolute ILC marker
in humans because a majority of CD16 CD56bright NK cells in pe-
ripheral blood do express CD127. CD200R expression has been
1056 Cell 174, August 23, 2018
Figure 1. Development of ILCs
ILC development, mainly based on mouse ILCs
differentiation paths, is schematized. ILCs develop
from CILPs (common innate lymphoid pro-
genitors), which themselves differentiate from
CLPs (common lymphoid progenitors). CILPs can
differentiate into NK cell precursors (NKP) cells or
into CHILPs (common helper innate lymphoid
progenitors), which themselves give rise to LTiPs
(lymphoid tissue inducer progenitors) and ILCP
(innate lymphoid cell precursors). LTiPs differen-
tiate into LTis and ILCPs into ILC1, ILC2, or ILC3.
Each stage of differentiation is dependent on the
expression of the indicated transcription factors:
NFIL3 (nuclear factor IL-3 induced), Id2 (inhibitor of
DNA binding 2), TOX (thymocyte selection-asso-
ciated high mobility group box protein), TCF-1
(T cell factor 1), ETS1 (avian erythroblastosis virus
E26 homolog-1), GATA3 (GATA binding protein 3),
PLZF (promyelocytic leukemia zinc finger), T-bet
(T-box transcription factor), Eomes (Eomeso-
dermin), RUNX3 (runt-related transcription fac-
tor 3), RORa (RAR-related orphan receptor a),
Bcl11b (B cell lymphoma/leukemia 11B), Gfi1
(growth factor independent 1), RORgt (RAR-
related orphan receptor gt), and AhR (Aryl hydro-
carbon receptor). It has been shown in humans
that ILC1 subsets may originate from precursors
other than ILCPs (Fuchs et al., 2013), but the
identity of which remains unknown at this time.
shown to distinguish ILC1s from NK cells
in mice (Weizman et al., 2017). Another
marker of human NK cells is NKp80,
which is not expressed on ILC1s (Freud et al., 2016). ILC1s are
tissue-resident cells, whereas NK cells circulate in the blood-
stream (Peng et al., 2013; Gasteiger et al., 2015). In mice,
ILC1s are first detected before birth, whereas NK cells emerge
two to three weeks after birth (Diefenbach et al., 2014). There
are also differences in the production of and dependence on
transcription factors. In mice, ILC1s are strictly dependent on
Tbet, whereas NK cells are present in Tbet-deficient hosts
(Daussy et al., 2014). In addition, NK cells require the T-box fac-
tor Eomes, whereas ILC1s can develop in the absence of this
transcription factor. Eomes expression is, therefore, often used
as a marker for NK cells, although it can be expressed on a pro-
portion of ILC1s.
ILC2s
ILC2s are defined by their capacity to produce the type 2 cyto-
kines IL-4, IL-5, and IL-13 (Moro et al., 2010; Neill et al., 2010;
Price et al., 2010) and are tissue resident (Gasteiger et al.,
2015; Moro et al., 2016). They respond to the cytokines IL-25,
TSLP, and IL-33. ILC2s are involved in the innate immune
response to parasites, such as the helminth Nippostrongulus
brasiliensis. After resolving the infection, ILC2s help to repair
damaged tissues by producing AREG (Monticelli et al., 2011,
2015). ILC2s contain larger amounts of the transcription factor
GATA3 than the other ILC subsets, and absence of GATA3
inhibits the development and function of these cells (Hoyler
et al., 2012; Klein Wolterink et al., 2013; Furusawa et al., 2013;
Mjösberg et al., 2012). Although a classical marker for tissue-
resident ILC2s in mice is ST2, a component of the IL-33 receptor,
some tissue ILC2s do not express ST2 (e.g., skin), as ST2

expression can be impacted by the tissue of origin and the state
of the microenvironment. ILC2s present in human peripheral
blood lack ST2 (Bal et al., 2016), but human ILC2s, whether in
the peripheral blood or in tissues, selectively express the chemo-
attractant receptor expressed on Th2 cells (CRTH2) and high
levels of CD161 (Mjösberg et al., 2011).
ILC3s
ILC3s are abundant at mucosal sites and are involved in the
innate immune response to extracellular bacteria and the
containment of intestinal commensals (Cella et al., 2009; Luci
et al., 2009; Cupedo et al., 2009; Satoh-Takayama et al.,
2008; Buonocore et al., 2010; Sonnenberg et al., 2011, 2012;
Rankin et al., 2016). The predominant homeostatic cytokine
produced by ILC3s is IL-22, by which they maintain intestinal
homeostasis and promote the proliferation of intestinal stem
cells. In addition, ILC3s can regulate adaptive Th17 cell re-
sponses (Hepworth et al., 2013). In mice, ILC3s are dependent
on RORgt for their development and function (Satoh-Takayama
et al., 2008; Sanos et al., 2009; Buonocore et al., 2010), whereas
the IL-17A-producing ILC3 subset (but not the IL-22-producing
subset) is absent in RORC-deficient humans (Lim et al., 2017).
Two subsets of ILC3 can be distinguished on the basis of the
cell surface expression of NKp46 (in mice) and NKp44 (in hu-
mans) (Luci et al., 2009; Cupedo et al., 2009; Sanos et al.,
2009), i.e., the NCR+ ILC3. Both mouse and human ILC3s can
produce GM-CSF. In mice, NKp46+ ILC3s are dependent on
Tbet and can produce IFN-g (Sciumé et al., 2012; Klose et al.,
2013; Rankin et al., 2013). These cells develop after birth,
following microbial stimulation. Ex-vivo-isolated human ILC3s
do not produce IFN-g.
LTi Cells
LTi cells are crucial for the formation of secondary lymph nodes
and Peyer’s patches during embryonic development, through
the action of lymphotoxin (Mebius et al., 1997). These cells ex-
press c-Kit and CCR6, but not NCRs. Like ILC3s, they are strictly
dependent on RORgt. LTi cells and postnatal NCR- ILC3s are
Figure 2. Immune Function of ILCs
Some of the most well-known immune function of
each ILC subset is shown: NK cells and ILC1s
react to intracellular pathogens, such as viruses,
and to tumors; ILC2s respond to large extracellular
parasites and allergens; ILC3s combat extracel-
lular microbes, such as bacteria and fungi; and
LTis are involved in the formation of secondary
lymphoid structures. For each ILC subset, effector
molecules that can be produced upon activation
are indicated.
difficult to separate on the basis of marker
expression, but neuropilin (NRP-1), which
can be induced on human postnatal
NCR ILC3s may mark the capacity of
these cells to mediate the formation of ter-
tiary lymphoid structures (Robinette et al.,
2015; Shikhagaie et al., 2017). However,
lymphoid tissue-forming activity is not
unique to postnatal ILC3s/LTi cells, as
other lymphotoxin-producing cell types
may also be involved in this activity. LTi cells and ILC3s have
different developmental paths (Figure 1).
ILC Plasticity: A Key to ILC Heterogeneity
There is increasing evidence to suggest that like T helper cell
subsets, ILC subsets also display a certain degree of plasticity.
Thus, ILC subsets can change their phenotype and functional
capacities and this requires accessible polarizing signals in the
tissue in which conversion occurs, together with the expression
of cognate cytokine receptors and key transcription factors in
the responding ILCs. For example, fate-mapping and adoptive
transfer studies in mice have shown that gut CCR6–NKp46–
ILC3s can convert into IFN-g-producing NK1.1+NKp46+ ILC1s
via a CCR6–NKp46+ intermediate (Vonarbourg et al., 2010).
This process requires a decrease in RORgt expression (Vonar-
bourg et al., 2010), with a parallel increase in T-bet (Sciumé
et al., 2012; Klose et al., 2013; Rankin et al., 2013) and Notch
signaling (Lee et al., 2011; Viant et al., 2016; Chea et al., 2016).
IL-1b, IL-15 and IL-12 are likely the critical factors because
human IL-22-producing ILC3s can be converted into IFN-g-pro-
ducing ILC1-like cells if cultured in vitro with these cytokines
(Cella et al., 2010; Bernink et al., 2015). Recent studies indicate
that ILC2s can also convert into IFN-g-producing ILC1s both
in vitro and in vivo (Ohne et al., 2016; Bal et al., 2016; Silver
et al., 2016). T-bet and the IL-12 receptor (IL-12R) must be
induced for this conversion to occur (Lim et al., 2016). Further-
more, in vivo exposure of ILC2 to the cytokines IL-25 and IL-33
in mice appear to elicit distinct functional responses. Systemic
injections of IL-25 promote the generation of ILC2s, which pro-
duce IL-17 in addition to type 2 cytokines and were called inflam-
matory ILC2s (Huang et al., 2015). This transformation is depen-
dent on Notch signaling and RORgt expression (Zhang et al.,
2017). IL-25-responding ILC2s arise from resting intestinal
ILC2s in response to infection with helminths (Huang et al.,
2015; Neill et al., 2010). Unlike IL-33-responsive ILC2s, which
are tissue resident (Gasteiger et al., 2015; Moro et al., 2016),
Cell 174, August 23, 2018 1057
Table 1. Main Phenotypic Markers of the Different Subsets of Murine and Human ILCs
Mouse Human
NKp46 NKp46+ NKp44 NKp44+
NK ILC1 ILC2 LTi ILC3 ILC3 NK ILC1 ILC2 LTi ILC3 ILC3
Cell-surface CD45 + + + int + + CD45 + + ++ int + +
molecules CD127 (IL-7Ra) a b
+ ++ W W CD127 (IL-7Ra) –/+ e
+ + + +
CD161 (NK1.1) + + – – – –/+ CD161 (NK1.1) +/ + + +/ + +
ST2 (IL-33R) – nd +/ nd nd nd ST2 (IL-33R) +/ – +/ nd nd –
CD278 (ICOS) W nd ++ nd W W CD278 (ICOS) – nd + nd nd +
IL-17Rb (IL25R) – nd + – – – IL-17Rb (IL25R) – – + – nd –
CD294 (CRTH2) – nd + nd nd nd CD294 (CRTH2) – – + – – –
KLRG1 ++ – + – – – KLRG1 + – + – – –
CD117 (c-kit) - +/ +/ ++ W W CD117 (c-kit) –/W – +/ + + +
c
CD69 + nd nd nd nd CD69 W +/ nd nd nd nd
CD254 (RANKL) nd nd nd + + + CD254 (RANKL) – nd nd + + +
CD196 (CCR6) – nd – + +/ – CD196 (CCR6) – +/ +/ + +/ +/
CD335 (NKp46) + + – – – + CD335 (NKp46) + – – – -/W W/+
d
CD25 (IL-2Ra) –/W + +/ +/ +/ CD25 (IL-2Ra) +/ W + W +/ –/W
MHC-II – – + + + – MHC-II +/ nd +/ nd nd +/
IL23R – – nd + + + IL23R +/ +/ –/W + + +
IL1Rb – + nd + + + IL1R +/ + W + + +
CD122 + + W – – – CD122 + nd nd –/W W W
CD314 (NKG2D) + nd – – – + CD314 (NKG2D) + nd nd – -W –/W
Ly49 +/ +/ – – – – KIR +/ – – – – –
CD94 +/ nd +/ nd – +/ CD94 +/ – – – – –
Perforin + W – – – – Perforin + – – – – –
CD253 (TRAIL) – + nd nd nd nd IL12Rb + + – – – +/
d
Sca-1 (Ly6a) + + – nd + CD194 (CCR4) nd +/ + nd nd nd
CD49d nd nd – nd + + CD56 + – – –/W +/ +/
(integrin a4b7)
a
CD49a + nd nd nd nd CD183 (CXCR3) nd + nd nd nd nd
(integrin a1b1)
CD90 (Thy1) +/ + + + + + CD337 (NKp30) + + + +/ +/ +/
f d
CD160 + nd nd nd nd CD336 (NKp44) – – – – +
g
CD103 – nd nd nd nd CD16 +/ – – – – –
CD200R – + nd nd nd nd NKp80 + – nd nd nd nd
Transcription Tbet + + – – +/ + Tbet + + – – – –
factors Eomes + +/– – – – – Eomes + +/– – – – –
RORgt – – – + + + RORgt – –/W –/W + + +
GATA3 –/W –/W + –/W –/W –/W GATA3 –/W –/W + –/W –/W –/W
AhR – nd nd + + + AhR –/W W + + + +
RORa nd nd + nd nd nd
The expression of certain markers varies according to the organs. int, intermediate expression; W, weak expression; nd, not determined. ‘‘+/ ’’ means
that expression is detected in some, but not all, cells.aNot expressed by NK cells of liver, intestine, skin, uterus, salivary gland, bone marrow, or lymph
nodes. Expressed by NK cells in the thymus and in some spleen populations.
b
Expressed by the majority of ILC1, except for liver populations and intraepithelial gut ILC1.
c
Expressed by NK cells of the intestine, uterus, and thymus, but not the spleen and liver.
d
Expressed by activated cells.
e
Expressed by the majority of ILC1, except for tonsil and intraepithelial ILC1.
f
Not expressed by NK cells of the spleen, liver, uterus, or blood. Expressed by NK cells in the gut.
g
Not expressed by liver or spleen NK cells. Expressed by NK cells in the blood.

1058 Cell 174, August 23, 2018

IL-25-responsive ILC2s circulate in the bloodstream and can
migrate to effector sites, where they help to protect tissues
following infection (Huang et al., 2015). It remains unclear
whether these ILC2s constitute two different subsets or different
activation states of the same plastic cell type. Along this line, a
subset of IL-10-producing ILCs has been identified as regulatory
ILCs (ILCregs) (Wang et al., 2017). These cells are claimed to
develop directly from CHILP rather than from ILCp in an ID3-
dependent manner and to be distinct from other ILC subsets.
As ILC2s can develop into IL-10-producing cells (Gury-BenAri
et al., 2016; Seehus et al., 2017), further investigation is needed
to fully understand the nature and potential significance of
ILCregs. Finally, human and mouse cytotoxic NK cells also ac-
quire ILC1-like features in response to enhanced TGF-b
signaling (Gao et al., 2017; Cortez et al., 2017).
In addition to cytokine receptors and their downstream
transcription factors, ILC plasticity requires defined chromatin
regions, such as cis-acting enhancers and silencers of gene
expression, to be accessible to transcription factors. Recent
studies have investigated chromatin status in human and mouse
ILCs, comparing the results obtained to published findings for
the CD4 T helper cell counterparts of these cells (Koues et al.,
2016; Shih et al., 2016). Accessible chromatin regions were
assessed by ATAC-seq. It was then determined whether these
regions were active or simply poised for activation, by assessing
histone H3-K27 acetylation or the binding of the regulatory factor
p300. One distinctive feature of the ILC regulome is that
regulatory regions controlling the expression of signature
cytokine genes are already poised or active in ILCs, whereas
identical regulatory regions in CD4 T helper cells become acces-
sible only after activation by cytokine signals or infection (Shih
et al., 2016). These results suggest that ILC regulomes are
more prone to dynamic changes in response to the microenvi-
ronment. Recently it was shown that transition of ILC2s to
ILC1s by IL-1b and IL-12 is marked by an atypical chromosomal
landscape in which the locus encoding IFN-g and the locus
encoding IL-5 and IL-13 are simultaneously accessible (Ohne
et al., 2016).
It is becoming clear that this malleability of ILCs directs the
heterogeneity of these cells in the tissues and this may be impor-
tant for effective immune responses and may also play roles
in inflammatory diseases, such as Crohn’s disease (Bernink
et al., 2015) and chronic obstructive pulmonary disease (Silver
et al., 2016; Bal et al., 2016). However, the exact functional
impact of ILC plasticity is still incompletely understood and re-
mains an active area of research.
ILCs and Metabolism
There is increasing evidence to link ILCs with metabolic homeo-
stasis, dietary stress and obesity. Malnutrition and gluttony can
lead to dysregulated ILC-mediated responses both through the
availability of specific dietary nutrients, and by altering immune
homeostasis as adipose tissue energy stores expand and con-
tract with nutrient availability.
Regulation of ILCs by Dietary Nutrients
The ratios of ILC populations, and their activation states, can be
profoundly influenced by the availability of environmental micro-
nutrients and diet-derived metabolites (Figure 3A). Signaling via
the aryl hydrocarbon receptor (AhR) transcription factor in
response to tryptophan metabolites is required to maintain
IL-22 expression and intestinal homeostasis (Lee et al., 2011;
Kiss et al., 2011). Consequently, an absence of AhR ligation im-
pairs immunity to intestinal bacterial infections (Lee et al., 2011;
Kiss et al., 2011). Similarly, a deficiency of dietary vitamin A re-
sults in abnormally small numbers of ILC3s, a shortfall in IL-22
production and greater susceptibility to gastrointestinal Citro-
bacter rodentium infection (Spencer et al., 2014). The vitamin A
metabolite retinoic acid (RA), which is produced predominantly
by dendritic cells, at least in the intestinal lamina propria, pro-
motes the expression of gut-homing receptors on ILC1s and
ILC3s (Kim et al., 2015), and enhances ILC3 function by upregu-
lating RORgt (van de Pavert et al., 2014) and IL-22 (Mielke et al.,
2013). Conversely, RA suppresses ILC2 proliferation by downre-
gulating IL-7Ra (Figure 3A). Accordingly, ILC2 numbers increase
during periods of vitamin A deficiency, increasing the efficiency
of parasitic helminth expulsion (Spencer et al., 2014). It has
been suggested that during periods of micronutrient scarcity,
ILC2s are sustained by fatty-acid metabolism, which maintains
the production of IL-13 (Wilhelm et al., 2016). Thus, host dietary
status can substantially modify the balance of the ILC response
and alter the predisposition to infection, selectively optimizing
immune responses to promote survival during periods of nutrient
limitation. There are presumably subtle local adjustments to
the balance of available nutrients within tissues, to allow the im-
mune system to respond appropriately to the relentless stream
of diverse immune challenges posed by co-infections and the
commensal microbiome. A more thorough understanding of
these complex processes might facilitate the therapeutic manip-
ulation of immune responses through dietary refinements and
nutrient supplementation.
ILCs in Metabolic Tissues
Adipose tissues contain many types of immune cells, which
reside among the adipocytes. Recent studies have demon-
strated that ILC2s contribute to the maintenance of metabolic
homeostasis by supporting the type-2 immune environment
characteristic of the adipose tissue of lean individuals. Dysregu-
lation of this pathway leads to obesity with persistent, low-grade
type 1 inflammation. ILC2s reside constitutively in visceral
adipose tissue (VAT), where they are maintained by the expres-
sion of IL-33 (Brestoff et al., 2015). Here, they produce IL-5 to
sustain eosinophils, and IL-13 to polarize M2 macrophages
and regulate adiposity and insulin resistance (Brestoff et al.,
2015; Molofsky et al., 2013) (Figure 3A). ILC2s appear to regulate
adiposity and caloric expenditure through several different
mechanisms. For example, their production of IL-4 and IL-13 is
reported to induce pre-adipocyte differentiation into beige adi-
pocytes (Lee et al., 2015). Additionally, ILC2s have been shown
to express the endopeptidase proprotein convertase subtilisin/
kexin 1 (Pcsk1), which can process the proenkephalin A
produced by ILC2s to yield methionine-enkephalin (MetEnk)
peptides, which induce UCP1 in adipocytes (Brestoff et al.,
2015). The treatment of mice with exogenous MetEnk induces
beiging, thus increasing caloric consumption, although the phys-
iological contribution of ILC2-derived MetEnk remains unclear
(Figure 3A). Furthermore, in addition to the roles of ILC2s in
VAT, IL-33-stimulated ILC2s in the pancreas can drive dendritic
Cell 174, August 23, 2018 1059

cells to secrete retinoic acid, which promotes the secretion of
insulin by b cells and glucose regulation (Dalmas et al., 2017).
During the maintenance of a lean state, heterogeneous ILC1/
NK populations may also be found in the VAT, in which they are
thought to help maintain homeostasis. It has been suggested
that this may involve the targeted cytotoxic-killing of adipose
tissue macrophages, although, counter-intuitively, the target-
ing of beneficial M2 macrophages has also been reported
(Boulenouar et al., 2017), and modulations in M2 macrophages
have not been reported in lean ILC1-deficient mice. With the
onset of obesity, there is a shift toward an inflammatory envi-
ronment in which IFN-g-producing ILC1/NK cells accumulate
in the VAT and prime M1 pro-inflammatory macrophage polar-
ization, promoting insulin resistance (Lee et al., 2016; O’Sulli-
van et al., 2016; Wensveen et al., 2015) (Figure 3A).
The extent to which ILCs sense and orchestrate changes in the
adipose tissues remains unclear, as does the extent to which
their activity simply reinforces and stabilizes established immu-
noregulatory pathways. Nevertheless, ILC subsets clearly help
1060 Cell 174, August 23, 2018
Figure 3. Functions of ILCs beyond Immunity
(A–C) The regulation of ILC function by nutrients (A),
their role in tissue repair (B), and the links between
ILCs and the nervous system (C) are schematized.
to maintain the delicate immune balance
within adipose tissue and are dysregu-
lated in obesity.
ILCs in Tissue Remodeling and
Repair
ILCs are largely tissue-resident cells
(Gasteiger et al., 2015). This remarkable
tissue dwelling property of ILC provides
an interesting framework for understand-
ing the biology of ILCs that seem to fulfill
functions in organ homeostasis and
repair, not conventionally assigned to
the immune system. Tissue residency
does not preclude local migration how-
ever, and ILC3s have been observed to
crawl into and out of cryptopatches at
steady state, with increased egress into
the tissue during the onset of inflamma-
tion (Pearson et al., 2016). ILCs may
follow local chemokine gradients and,
in this manner, migrate to local inflamma-
tory foci, returning to newly formed
lymphoid structures at the end of an infec-
tion. One puzzle has been how the low
abundance of ILCs in certain tissues
can exert any effect in vivo. Localization
and concentration within immune clusters
and local migration in response to envi-
ronmental cues may allow an exponential
increase in the potency of ILC-secreted
cytokines at sites of tissue damage or
infection.
In addition to migration within adult tissues, LTi cells, that are
required for lymph node and Peyer’s patch formation, actively
migrate to the lymphoid organ primordia to promote lymphoid
tissue development (Veiga-Fernandes et al., 2007). It is impor-
tant to note that ILCs are therefore populating organs and tissues
often early in ontogeny. LTi cells seed tissues already early
during embryonal development (Mebius et al., 1997). The inter-
dependency of the co-development of organs and components
of the innate immune system has not been addressed in much
detail and will be an important trajectory for future research.
The deep rooting of ILCs in tissues has led to a new appreciation
of unsuspected roles of components of the innate immune
system in basic developmental and physiological processes
such as tissue homeostasis, morphogenesis, growth, and
regeneration. On these aspects, ILCs and tissue-resident mac-
rophages might share potential similarities, as they both develop
in the mouse, both duringembryonic life and home in tissues
where they can proliferate and differentiate into mature effector
cells (Bando et al., 2015).
ILC2s, Tissue Repair, Fibrosis, and Tissue Remodeling
for Helminth Expulsion
Type 2 immunity has been largely discussed in the context of im-
munity to worm infections and of pathogenesis of allergies. It has
been proposed that a fundamental property of type 2 immunity is
to deal with organisms too large to ingest, break down and digest
(Palm et al., 2012). Therefore, they need to be expelled across
barrier surfaces, a process requiring extensive tissue remodeling.
Recently a new regulatory loop for ILC2 function has been found
that is required to expel worms in process referred to as ‘‘weep-
and-sweep.’’ In the intestine, a secretory lineage of epithelial
cells, tuft cells or brush cells, secrete high levels of IL-25 following
helminth infection that activates ILC2. ILC2, in turn, secrete IL-13
driving the differentiation of epithelial cells toward the secretory
lineage likely by modulating Notch signaling in epithelial cells.
Thus, this feedforward loop instructs tissue remodeling required
for expulsion of large multicellular pathogens (von Moltke et al.,
2016; Howitt et al., 2016; Gerbe et al., 2016).
Immune activation comes at the price of collateral tissue dam-
age. The best studied example may be influenza infection where
most of the clinical sequelae are believed to be a consequence of
immune system activation. ILC2s have important roles in limiting
tissue damage after infection by the production of ligands for the
epithelial growth factor receptor, such as AREG. AREG pro-
duced by ILC2s has been shown to control proliferation and
differentiation of epithelial cells which was required for epithelial
repair following influenza infection (Monticelli et al., 2011; Zaiss
et al., 2015). Similarly, the extensive tissue damages after hel-
minth migration and expulsion also lead to the production of
AREG, an important factor for timely repair (Monticelli et al.,
2015) (Figure 3B). It is possible that the same signaling circuitry
and the same cytokines (IL-13 and AREG) that promote tissue
repair can become dysregulated in the presence of chronic
inflammation and an altered cytokine milieu to promote fibrotic
responses, including myofibroblast differentiation, proliferation,
and extracellular matrix deposition.
It may be a fundamental property of type 2 immunity and in
particular of ILC2s to instruct remodeling of extracellular matrix.
Indeed, ILC2s are a relevant source of IL-5 early during immune
responses and are indispensable for the recruitment of eosino-
phils and the programing of alternatively activated macrophages
(also referred to as M2 macrophages) (Molofsky et al., 2013).
Upon muscle injury, eosinophil-derived IL-4 induces the prolifer-
ation of fibro/adipogenic progenitors (FAPs), thereby preventing
their differentiation into adipocytes. In this way, FAPs supported
myogenesis and the regeneration of skeletal muscle after injury
driven by a type 2 immune program (Heredia et al., 2013). Mech-
anisms controlling ILC2 activities are also important in regaining
homeostasis after inflammation. STAT1 signals downstream of
type I and type II interferons and of IL-27 are critical for suppress-
ing ILC2 functions (Duerr et al., 2016; Molofsky et al., 2015; Moro
et al., 2016), whereas STAT5 signals downstream of IL-2, IL-9,
and TSLP enhance activation of ILC2, leading to steroid resis-
tance (Kabata et al., 2016).
ILC1s and ILC3s in Repair
Type 1 and type 3 responses that are orchestrated by ILC1s and
ILC3s, involve phagocytes that release oxygen radicals and
enzymes to lethally damage pathogens, kill infected cells,
and engulf and digest dying cells and extracellular matrix.
Such responses come therefore at a cost for the host’s affected
tissue, and must be limited in time by repair responses that are
coordinated by type 2 responses. Nevertheless, in order to be re-
paired, a tissue has to be cleansed of microbes, dying cells and
debris, and therefore, destructive responses that involve ILC1s
and ILC3s are necessary to proceed to repair before the tissue
can return to homeostasis (Figure 3B).
Paradoxically at first sight, type 3 responses play an important
role, not in tissue repair, but in protection from tissue damage. In
particular, epithelial barriers are reinforced by type 3 responses
in order to resist damage by microbes. IL-22, produced mainly
by ILC3s, induces epithelial cells to express anti-bacterial
peptides such as Reg3g and Reg3b, as well as antiviral proteins
through reinforcement of interferon-l signaling (Hernández et al.,
2015). In addition, IL-22 stabilizes the epithelial barrier by pro-
tecting epithelial cells and Lgr5+ stem cells from apoptosis
induced by irradiation, chemotherapy or graft versus host dis-
ease through the activation of STAT3 (Aparicio-Domingo et al.,
2015; Lindemans et al., 2015). IL-22 also protects thymic epithe-
lial cells from irradiation (Dudakov et al., 2012) and hepatocytes
from acute inflammation (Zenewicz et al., 2007) (Figure 3B).
While constitutive absence of IL-22 enhances inflammation-
driven colorectal cancer (Huber et al., 2012), the proliferation-
promoting effect of IL-22 on epithelial cells can also sustain the
progression of colon cancer (Kirchberger et al., 2013; Hernandez
et al., 2018).
Neuronal Regulation of ILC Responses
The regulation of immune responses has been shown to involve
the brain and nervous system. The autonomic nervous system,
through its neurotransmitters and neuropeptides, and the
hypothalamic-pituitary-adrenal axis work in parallel to modulate
inflammation and maintain homeostasis. Recent studies have
described a complexity of interactions between ILCs and the
nervous system.
Regulation of NK Cells and ILC1s by the Hypothalamic-
Pituitary-Adrenal Axis
The neuroendocrine system can sense changes in the environ-
ment. It then acts to restore homeostasis by modulating the
strength and duration of inflammatory reactions through rapid,
pleiotropic mechanisms. Activation of the hypothalamic-pitui-
tary-adrenal axis leads to glucocorticoid release in the blood.
NK cells and ILC1s express the glucocorticoid receptor, a tran-
scription factor involved in the regulation of multiple pathways
(Quatrini et al., 2017). Glucocorticoid receptor signaling in these
cells inhibits IFN-g production by NK cells in the liver and spleen
and by ILC1s in the liver and is required for host resistance to
endotoxic shock. This regulation is required for the development
of IL-10-dependent endotoxin tolerance. By contrast, disruption
of this pathway results in high levels of IFN-g culminating in
endotoxin-induced septic shock and death (Quatrini et al.,
2017). During mouse cytomegalovirus infection, regulation of
NK cell functions by glucocorticoid receptors is also required
for host resistance to infection. This regulation occurs through
the tissue-specific expression of PD1, an inhibitory receptor,
on spleen NK cells. Binding of PD1 to its ligands downregulates
IFN-g production. This inhibition prevents the excessive
Cell 174, August 23, 2018 1061
production that would otherwise result in a lethal IFN-g-depen-
dent spleen immunopathology, without impairing an effective
antiviral response (S. Ugolini et al., personal communication)
(Figure 3C).
Neuropeptides, Neurotransmitters, and ILC2s
Neurotransmitters and neuropeptides play a crucial role in
communication between the nervous and immune systems,
and many of these molecules are also produced directly by im-
mune cells. The ILCs of the intestine and lungs express receptors
for the neurotransmitters and neuropeptides produced in
these mucosal tissues. Indeed, various ILC subsets express
the b2AR (b2-adrenergic receptor) for epinephrine and norepi-
nephrine, the CHRM (cholinergic receptor muscarinic) for acetyl-
choline, the VPAC1/2 (vasoactive intestinal peptide receptor)
for VIP, the NMUR1 for neuromedin U (NMU) and CALCRL
(calcitonin receptor-like) for CGRP. ILC2s are subject to tight
regulation by neuropeptides. The principal role of VIP is the main-
tenance of homeostasis at mucosal barriers through the regula-
tion of IL-5 production (Nussbaum et al., 2013). CGRP signaling
in ILC2s is required for a full Th2 immune response in models of
allergen-induced asthma (Sui et al., 2018). NMU plays no signifi-
cant role in homeostatic conditions, but its induction upon hel-
minth infection leads to a type 2 protective immune response in
the intestine through intrinsic ILC2 regulation. NMU has also
been shown to act in synergy with IL-25 in the induction of
cytokine production by lung ILC2s (Cardoso et al., 2017; Klose
et al., 2017; Wallrapp et al., 2017) (Figure 3C). While the role of
catecholamines on NK cells appears complex and remains to
be dissected in depth, it has been recently demonstrated that
b2AR stimulation intrinsically suppresses the proliferation and
effector functions of ILC2s. ILC2 responses and type 2 inflamma-
tion are, thus, downregulated following exposure to the parasite
N. brasiliensis in the gut and by intranasal IL-33 administration or
exposure to Alternaria alternata extract in the lungs (Moriyama
et al., 2018) (Figure 3C). Other interactions between ILC2s and
neurons also occur in the mucosal tissues of the respiratory tract.
Indeed, ILC2s have been observed very close to SNAP-25+ nerve
fibers on lung sections (Wallrapp et al., 2017), and lung IL-5-pro-
ducing ILC2s have been identified in collagen-rich regions close
to the confluence of medium-sized blood vessels and airways
(Nussbaum et al., 2013). IL-5-producing ILC2s have also been
found close to pulmonary neuroendocrine cells in the airway
branch junctions at which particles entering the airways become
concentrated (Sui et al., 2018). Thus, ILC2s appear to be located
at strategic points in the mucosal tissues of the airways, acting
with the neuroendocrine system to patrol the airways, recruiting
circulating immune cells to sites of damage or in response to
pathogen invasion.
ILC3s and Neuroimmune Cell Units
Neuroimmune cell units (NICUs) have recently been described as
defined small cellular networks in which immune and neuronal
cells are found at the same anatomic site, interact functionally,
and participate in tissue homeostasis and integrity (Veiga-Fer-
nandes and Artis, 2018). The RET neurotrophic factor receptor
is a typical example of such communication between the cells
of the nervous and immune systems. RET is a receptor tyrosine
kinase activated by glial cell-derived neurotrophic factor and
related proteins. It plays crucial roles in hematopoiesis, Peyer’s
1062 Cell 174, August 23, 2018
patch formation and the development of the gut nervous system
(Patel et al., 2012; Veiga-Fernandes et al., 2007). RET is strongly
expressed in the ILC3s of the lamina propria in the adult gut.
These cells are located within cryptopatches, close to stellate
projections of the lamina propria glial cells. These glial cells are
the principal producers of RET ligands, which are induced in
response to commensal products and alarmins. This essential
glial cell-ILC3 pathway conditions the reactivity of epithelial cells
and regulates intestinal defenses against Citrobacter rodentium
infection by inducing the production of IL-22 by ILC3s in response
to RET ligands (Ibiza et al., 2016) (Figure 3C). Communications
between the central nervous system and the intestine are also
mediated by the so-called ‘‘gut-brain axis,’’ through projections
from the sympathetic and parasympathetic systems, and via
the hypothalamic pituitary adrenal axis. The vagus nerve is the
principal extrinsic parasympathetic nerve connecting the brain-
stem and gut. ILC3s are located close to choline acetyltransfer-
ase-positive cells in the greater omentum (Dalli et al., 2017),
suggesting that crosstalk between ILC3s and cholinergic vagus
nerve fibers occurs not only in the intestine but also in the perito-
neum. ILC3s can also be regulated by the cholinergic receptors
muscarinic (Chrm)1, 2, 4 and 5, and both mouse and human
ILC3s respond to acetyl-chloline stimulation by producing the
lipid mediator PCTR1 (16R-glutathionyl, 17S-hydroxy-4Z, 7Z,
10Z, 12E, 14E, 19Z-docosahexaenoic acid) (Dalli et al., 2017)
(Figure 3C). PCTR1 belongs to a family of proresolving molecules
that control the clearance of bacterial infections by phagocytes
and attenuate collateral tissue injury and inflammation. Thus, tis-
sue-resident ILC3s actively regulate macrophage and granulo-
cyte responses to infection through the release of cytokines,
such as GM-CSF (Mortha et al., 2014), and by the production of
proresolving mediators under vagal system control. The direct
role of vagus stimulation in ILC3 control remains to be shown.
Conclusions and Perspectives
After 10 years of intensive research, the field of ILC biology
has provided a new vision on the organization of the immune
response. Nevertheless, several key questions remain to be
addressed.
ILC plasticity may be essential to shape and calibrate ILC
responses to different types of pathogenic stimuli. However,
several fundamental questions remain to be addressed:
(1) When does ILC plasticity arise? Does it occur at all stages of
ILC differentiation or is it progressively lost toward the final
stages? How to discriminate cell plasticity from various cell acti-
vation states? (2) Given that Th cells often display mixed Th1/
Th17 polarization, are there ILCs with a mixed cytokine secretion
pattern? (3) What epigenetic circuits are activated and silenced
during plastic ILC responses to a changing microenvironment?
(4) Is ILC conversion irreversible, or can ILCs repeatedly trans-
form after restimulation with polarizing cytokines? (5) Given
that infections, inflammation, and autoimmunity induce the
release of inflammatory cytokines into the tissue environment,
is ILC conversion enhanced under these conditions? (6) Is this
plasticity—the functional capacity of converted ILCs—essential
to fight infections and autoimmunity?
Compelling data in human and in the mouse indicate that ILCs
are involved in both inflammatory disorders and immunological
repair (Ebbo et al., 2017). The absence of immunodeficiency in
ILC-deficient patients in conditions of modern hygiene and med-
icine led to the proposal that ILCs are dispensable for protective
immunity if T and B cell functions are preserved (Vély et al.,
2016). Thus, the precise roles of ILCs in immunity and their dialog
with the other components of the multilayered immune response
await further analysis. Along this line, the role and importance of
ILCs in protective immunity in adult humans or wild-type mice,
where many tissue-resident adaptive memory cells share space
with ILCs, remains to be established. However, the roles of ILCs
in adapting tissue physiology to changes in the environment
have inspired research into processes that are not convention-
ally associated with the immune system. Further exploration of
these pathways may likely reveal unsuspected pathways by
which immune system workings might be harnessed to improve
health and health span.
Finally, the role of ILCs in the onset and/or maintenance of
inflammation, their preferential homing to mucosal tissues, and
the expression of several checkpoint receptors on their surface
should encourage researchers to explore the ILCs’ manipulation
in innovative therapies.
ACKNOWLEDGMENTS
We thank the members of all our laboratories for critically reading the
manuscript, Adeline Crinier for help with Table 1, Linda Quatrini and Sophie
Ugolini (CIML) for sharing unpublished results, and Marie-Alice Rarivoson
(Innate-Pharma) for help in formatting the manuscript.
Research in the Artis lab is supported by the NIH, the Crohn’s and Colitis
Foundation, the Burroughs Wellcome Fund, the Cure for IBD, and the Jill
Roberts Institute. M.C. is supported by the US NIH (UO1 AI095542, RO1
DE025884, and RO1 DK103039).The Diefenbach laboratory is supported by
the European Research Council (ERC) (311377 - NUTRIMMUNE), the Priority
Program 1937 ‘‘Innate Lymphoid Cells’’ of the Deutsche Forschungsgemein-
schaft (DFG), the Einstein Foundation Berlin, and the Berlin Institute of Health.
The Eberl lab is supported by grants from ANR, FRM, CCFA, Rainin Foundation
and the Institut Pasteur. Research in the Koyasu laboratory is supported by a
Grant-in-Aid for Scientific Research (A) (16H02631). Research in the Locksley
laboratory is supported by the HHMI, the NIH, and the SABRE Center at
UCSF. Research in the McKenzie laboratory is supported by funding from
the MRC (U105178805) and the Wellcome Trust (100963/Z/13/Z). The Di Santo
laboratory receives grants from the Institut Pasteur, Inserm, the Agence Natio-
nale de la Recherche, the Ligue Nationale contre le Cancer, and the European
Research Council (ERC) under the European Union’s Horizon 2020 Research
and Innovation Program (695467 - ILC_REACTIVITY). The Spits lab is sup-
ported by an advanced ERC grant (341038-AsthmaVir). Research in the Vivier
laboratory is supported by funding from the European Research Council (ERC)
under the European Union’s Horizon 2020 Research and Innovation Program
(694502-TILC), the Agence Nationale de la Recherche; Equipe Labellisée ‘‘La
Ligue,’’ Ligue Nationale contre le Cancer, MSDAvenir, and Innate Pharma
and institutional grants to the CIML (INSERM, CNRS, and Aix-Marseille Univer-
sity) and Marseille Immunopôle.
DECLARATION OF INTERESTS
E.V. is an employee of Innate-Pharma; the other authors declare no competing
financial interests.
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