Nri 3349

The orchestration of immune responses by T cells
through their release of a complex repertoire of

cytokines is crucial for adaptive immunity to infec-
tion. Coffman, Mosmann and others defined different
Thelper (T
H
) cell subsets based on their distinct cytokine
secretion profiles. T
H
1 cells, which produce interferon-
(IFN), interleukin-2 (IL-2) and lymphotoxin- (LT),
drive type 1 immune responses that protect against
intracellular pathogens, but they are also implicated in
various autoimmune diseases. By contrast, T
H
2 cells are
typically defined by their secretion of IL-4, IL-5, IL-9
and IL-13, and contribute to type2 immune responses.
Such responses are required for controlling extracellular
parasite infections, but they are also responsible for the
immunopathology that develops in patients with allergy
and asthma. Furthermore, we now recognize that addi-
tional T
H
cell subsets including T
H
17 cells and T fol-
licular helper cells (T
FH
cells) also have bespoke roles
in regulating different aspects of the immune response
through their distinct cytokine secretion profiles.
Recently, it has become clear that, in addition to
these adaptive lymphoid cell sources of cytokines,
there are important innate lymphoid cell (ILC) sources.
These previously unappreciated ILCs produce many
T
H
cell-associated cytokines, but they do not express
cell-surface markers that are associated with other
immune cell lin eages (TABLE 1). Furthermore, these
lineage marker-negative (LIN
) ILC subsets do not

express a Tcell receptor and thus do not respond in an
antigen-specificmanner.
A consortium of experts in the field has now proposed
that the term innate lymphoid cell should be used to
encompass the LIN
ILCs, natural killer (NK) cells and

lymphoid tissue-inducer (LTi) cells
1
. Furthermore, it has
been suggested that ILCs be further divided into three
subsets group 1 ILCs (comprising ILC1s and NK
cells), group 2 ILCs (comprising ILC2s) and group 3
ILCs (comprising ILC3s and LTi cells) based on their
ability to produce type1, type2 and T
H
17 cell-associated
cytokines, respectively (FIG.1). In this Review, we discuss
the developmental relationships of ILCs and summarize
their functional roles in protective immunity to infections
and their pathological roles in allergic and auto immune
diseases. As the immune functions of NK cells and LTi
cells have been reviewed elsewhere, this article concen-
trates on the more recently defined LIN
ILCs, with a
particular focus on the ILC2 and ILC3 populations.
ILC subsets
Group 1 ILCs. The group 1 ILCs comprise ILCs such as
NK cells that produce type1 cytokines, notably IFN
and tumour necrosis factor (TNF). NK cells were first
identified in 1975 as innate effector lymphocytes that
exhibit cytotoxic activity towards tumour cells
2,3
. Since
then, their roles in tumour surveillance, the elimination
of virus-infected cells and the amplification of inflam-
matory responses have been well documented
4
. Crucial
to their function is their capacity to induce granule-
mediated cytotoxicity through their expression of per-
forin and granzymes, and their ability to secrete the
pro-inflammatory cytokines IFN and TNF. NK cells
are dispersed in secondary lymphoid organs, blood and
peripheral organs, and they recognize and kill target cells
through the expression of a series of activating and inhib-
itory receptors on their surface, including the activating
receptors NKp46 (also known as NCR1) and NK1.1 (also
known as KLRB1C). Conventional NK cells arise in the
bone marrow, but NK cells can also develop in the thy-
mus, and the two types of NK cell population have differ-
ing growth factor requirements for their development
5
.
The diverse roles of NK cells have been reviewed exten-
sively elsewhere and so here we focus predominantly
on their developmental pathway and how NK cells are
related to the more recently identified ILC lineages.
MRC Laboratory of Molecular
Biology, Hills Road,
Cambridge, CB2 0QH, UK.
Correspondence to A.N.J.M.
e-mail:
anm@mrc-lmb.cam.ac.uk
doi:10.1038/nri3349
Published online
7 January 2013
Type1 immune responses
Type1 immune responses are
characterized by the
production of cytokines such
as interferon-, interleukin-2,
tumour necrosis factor and
lymphotoxin- by various
immune cells, including
Thelper 1 cells, neutrophils,
macrophages and NK cells.
Such responses protect against
intracellular pathogens and are
also implicated in several
autoimmune diseases.
Type2 immune responses
Type2 immune responses are
characterized by the secretion
of cytokines such as
interleukin-4 (IL-4), IL-5, IL-9
and IL-13 by various immune
cells, including T helper 2 cells,
eosinophils, basophils, mast
cells and ILC2s. Such
responses are required for
controlling extracellular
parasite infections, but they
are also responsible for the
immunopathology that
develops in patients with
allergy and asthma.
Innate lymphoid cells how did we
miss them?
Jennifer A.Walker, Jillian L.Barlow and Andrew N.J.McKenzie
Abstract | Innate lymphoid cells (ILCs) are newly identified members of the lymphoid lineage
that have emerging roles in mediating immune responses and in regulating tissue homeostasis
and inflammation. Here, we review the developmental relationships between the various
ILC lineages that have been identified to date and summarize their functions in protective
immunity to infection and their pathological roles in allergic and autoimmune diseases.
REVIEWS
NATURE REVIEWS | IMMUNOLOGY VOLUME 13 | FEBRUARY 2013 | 75
FOCUS ON THE INBETWEENERS: INNATE-LIKE LYMPHOCYTES
2013 Macmillan Publishers Limited. All rights reserved
T
H
17 cells
A subset of CD4
+
Thelper cells
that secrete predominantly the
pro-inflammatory cytokine
interleukin-17A and have been
implicated in the pathogenesis
of many chronic inflammatory
disorders.
T follicular helper cells
(T
FH
cells). A subset of CD4
+

helper Tcells that interact with
Bcells within germinal centres
to provide co-stimulatory
signals and regulate the
development of antigen-
specific Bcell immune
responses.
In addition to NK cells, other IFN-secreting ILCs have
been described; the new nomenclature proposes that these
cells be referred to as ILC1s
6
. ILC1s are weakly cytotoxic
and are closely related to, and appear to arise from, ILC3s,
as described below. However, the provenance of such
additional group1 ILC subsets remains to be established
rigorously to determine whether they simply represent
an alternative differentiation state of ILC3s or NKcells.
Group 2 ILCs. The existence of an innate immune cell
type that produces type2 cytokines was first postu-
lated after the discovery that intranasal administra-
tion of IL-25 still induces the production of IL-5 and
IL-13 in Rag2
/
mice, which lack conventional B and
Tcells
7,8
. Subsequently, a non-B, non-Tcell population
that responded to IL-25 and provided a crucial innate
source of type 2 cytokines at the onset of helminth
infection was identified
9
. In 2010, three reports
1012

further characterized these type2 cytokine-producing
ILCs and showed that they are present in the mes-
enteric fat-associated lymphoid clusters, mesenteric
lymph nodes, spleen, liver and intestines. They were
identified subsequently in the airways
1317
and Peyers
patches (J.A.W., unpublished observations). These cells
are variably termed natural helper cells (NHCs), nuo-
cytes and innate helper 2 (I
H
2) cells in the literature,
but it was recently agreed that the term ILC2s should
be used to refer to all ILCs that produce predominantly
type2 cytokines
1
. ILC2s require the transcription fac-
tors retinoic acid receptor-related orphan receptor-
(ROR)
18,19
and GATA-binding protein3 (GATA3)
20,21
,
and they have key roles in antihelminthic responses and
allergic lung inflammation. ILC2s express characteristic
surface markers (TABLE1) and chemokine receptors, such
as CXC-chemokine receptor 6 (CXCR6), CXCR4 and
CC-chemokine receptor 9 (CCR9), which are involved
in the homeostatic distribution of lymphoid cells to
specific organ sites
22
.
Following the discovery of ILC2s in mice, the search
for human equivalents began. The first report of human
ILC2s came from studies that screened human adult and
fetal gut tissue for the presence of LIN
IL-7R
+
CD45
int

or LIN
IL-7R
+
CD45
hi
cells
23
. A subsequent analysis
of the expression of RORt (which is required for the
development of other ILC lineages, as discussed below)
indicated that the LIN
IL-7R
+
CD45
int
cells express
high levels of RORt, whereas the LIN
IL-7R
+
CD45
hi

cells expressed low levels of this transcription factor.
The LIN
IL-7R
+
CD45
hi
population also expressed
transcripts encoding IL-13, IL-17 receptorB (IL-17RB;
a component of the IL-25 receptor), ST2 (also known
as IL-1RL1; a component of the IL-33 receptor) and
prostaglandin D2 receptor2 (also known as CRTH2),
suggesting that they represent the human ILC2 equiva-
lent. Indeed, such cells were also found in adult lungs
and blood and, notably, in elevated proportions in the
nasal polyps of patients with chronic rhinosinusitis
17,23
.
Group 3 ILCs: ILC3s. Almost simultaneously, three
groups reported the existence of an intestinal lymphoid
cell population that expresses the NK cell activating
receptor NKp46 but otherwise bears little functional
resemblance to conventional NK cells
2426
. This NKp46
+

population was dependent on the transcription factor
RORt, lacked cytotoxic effectors (such as perforin,
granzymes and death receptors) and did not produce
IFN or TNF, but instead expressed the cytokine IL-22
(REF.26). Fate-mapping approaches have demonstrated
that these cells are developmentally distinct from con-
ventional NK cells
27,28
. RORt
+
NKp46
+
cells are referred
to in the literature as NCR22 cells, NKp46
+
ILCs, ILC22s
and NKR-LTi cells, and additional names have been
used to describe equivalent populations in humans
2931
.
Under the new unified nomenclature, it is suggested
that these cells be termed NCR
+
ILC3s. This branch
of the ILC family resides predominantly in mucosal
Table 1 | Defining ILCs
ILC group ILC
lineage
Mouse Human Signature
cytokines
Group1
ILCs
ILC1s LIN
RORt
, RORt
fm+
(also
THY1
+
SCA1
+
)
LIN
CD56
+
NKp46
+
NKp30
+
NKp44
+
IL-7R
IFN
NK cells NKp46
+
NK1.1
+
(strain
dependent) CD122
+
NKG2D
+

CD161
+
CD16
+
CD11b
+
(REF.5)
CD122
+
NKG2D
+
CD161
+
KIR
+

(REF.99)
IFN, TNF, cytotoxic
effectors
Group2
ILCs
ILC2s LIN
ICOS
+
SCA1
+
IL-7R
+
ST2
var
(also
THY1
+
IL-17RB
+
CD25
+
)
LIN
IL-7R
+
CD45
hi
CD161
+
CRTH2
+
IL-5, IL-9, IL-13 and
small amounts of IL-4
Group3
ILCs
ILC3s LIN
RORt
+
NKp46
+
(also
THY1
+
IL-7R
int
KIT
int
CXCR5
CCR6
)
LIN
CD56
+
NKp46
+
NKp30
+
NKp44
+
IL-7R
+
IL-22
LTi cells LIN
RORt
+
NKp46
(also
THY1
+
IL-7R
hi
KIT
hi
CXCR5
+
CCR6
+
);
a proportion of LTi cells are CD4
+
LIN
IL-7R
hi
CD45
int
RORt
+
(also
CD7
+
CD161
+
CD4
CD94
)
LT, LT, IL-17A,
IL-22
CCR6, CC-chemokine receptor6; CXCR5, CXC-chemokine receptor5; ICOS, inducible T cell co-stimulator; IFN, interferon;
IL, interleukin; ILC, innate lymphoid cell; IL-7R, IL-7 receptor subunit-; KIR, killer cell immunoglobulin-like receptor; LIN
, lineage
marker-negative (defined in mice as negative for CD3, CD4, CD8, CD19, B220, CD11b, CD11c, FcRI, GR1 and TER119 antigen;
defined in humans as negative for CD1a, CD3, CD11c, CD34, CD123, TCR, TCR, BDCA2, FcRI, CD19, CD14 and CD16);
LT, lymphotoxin; LTi, lymphoid tissue-inducer; NK, natural killer; RORt, retinoic acid receptor-related orphan receptor-t;
RORt
fm+
, cells fate-mapped for Rorc expression (that is, those expressing GFP from the ubiquitously active Rosa26 locus after
a loxP-flanked STOP cassette has been excised by Cre recombinase that is expressed under the control of the Rorc locus on a
BAC transgene); TCR, Tcell receptor; TNF, tumour necrosis factor; var, variable.
REVI EWS
76 | FEBRUARY 2013 | VOLUME 13 www.nature.com/reviews/immunol
REVI EWS
Nature Reviews | Immunology
ID2
+
ILC
precursor
Notch,
GATA3,
ROR
LTi cell
Nuocyte,
NHC, I
H
2 cell
New
nomenclature
New group
nomenclature
ILC2 IL-5, IL-9, IL-13,
amphiregulin
Immunity to helminths
Wound healing
LTi cell Lymphotoxin,
IL-17, IL-22
NCR
+
ILC3 IL-22 Homeostasis of epithelia
Immunity to extracellular
bacteria
NCR
ILC3 IL-17,
IFN
bacteria?
IBD?
IBD
NK cell
NK cell
Group 1 ILCs
Group 3 ILCs
Group 2 ILCs
IFN

(high levels) Immunity to viruses and
intracellular pathogens
Tumour surveillance
ILC1
IFN

(low levels),
perforin,
granzymes
Immunity to viruses and
intracellular pathogens
Tumour surveillance
Inammatory
conditions,
IBD
Inammatory
conditions,
IBD
Allergy
and asthma
Mediators
produced Function
Disease
association
NK22 cell, NCR22 cell,
NKR-LTi cell, ILC22
ILC17
IL-7,
IL-23
IL-7
GATA3
IL-15
E4BP4
T-bet?
RORt
RORt
Notch
AHR
IL-7, IL-33,
IL-25, TSLP
Thymic NK cell
Conventional NK cell
Lymphoid tissue development
Intestinal homeostasis
bacteria
Inammation? IBD? IFN
OP9 cells
A bone marrow-derived
stromal cell line used to
support haematopoietic stem
cells and common lymphoid
progenitor cells during invitro
culture. The OP9DL1
variation of this cell line
ectopically expresses the
Notch ligand Delta-like 1,
which promotes the
differentiation of T cells.
tissues, particularly in the intestinal tract, where ILC3s
have a crucial role in mediating the delicate balance
between the symbiotic microbiota and the intestinal
immunesystem.
In humans, several cell types have been identified that
share features of both LTi and NK cells. It was shown
that culturing LTi cells either with IL-7 and FMS-related
tyrosine kinase 3 ligand (FLT3L) on stromal OP9 cells or
with IL-15 leads to the differentiation of a CD56
+
CD3
NKp46
+
NKp30
+
NKp44
+
population that does not express
killer cell immunoglobulin-like receptors (KIRs) or per-
forin and has only low levels of granzyme A expression
30
.
This population could be subdivided into ILC3-like and
ILC1-like subsets based on IL-7R expression. The LTi
cell-derived CD56
+
IL-7R
+
cells (the ILC3 subset) con-
tinued to express LT and LT, retained the capacity
to upregulate the expression of adhesion molecules on
mesenchymal cells, and expressed IL-22 and, to a lesser
extent, IL-17A. By contrast, the CD56
+
IL-7R
cells failed
to produce IL-17A and IL-22 and instead expressed IFN.
This suggests that they fall into the category of group1
ILCs, although they could not be further differentiated
into conventional NK cells
6
and it is unclear whether such
cells arise under physiological conditions.
Group 3 ILCs: LTi cells. LTi cells are an ILC subset
that appears to be closely related to ILC3s. However,
as discussed below, the exact relationship between LTi
cells and ILC3s is still controversial. LTi cells were first
identified as CD4
+
CD3
cells scattered among fetal

and neonatal lymph nodes
32,33
. These cells expressed
molecules required for the development of lymphoid
tissues, including LT and the common cytokine
receptor -chain (
c
; also known as IL-2R), and it
was therefore suggested that they might have crucial
roles in the generation of lymph nodes
32
and Peyers
patches
34
. Studies using a Rorc-EGFP (enhanced
green fluorescent protein) knock-in reporter mouse
demonstrated that the transcription factor RORt is
expressed by LTi cells and that, in its absence, LTi cells
are not generated and lymph nodes and Peyers patches
do not develop
35
. LTi cells are therefore essential for
lymphoid organogenesis during embryogenesis, and
they have subsequently been recognized as important
regulators of lymphoid tissue architecture after birth.
Indeed, they have roles in the development of crypto-
patches
36
, which are the precursors of isolated lym-
phoid follicles, and in the reconstruction of peripheral
lymph nodes following viral infection
37
. Furthermore,
Figure 1 | ILC subsets, functions and disease associations. Innate lymphoid cells (ILCs) differentiate from
haematopoietic stem cells, via an ID2
+
precursor cell, under the influence of cytokines such as interleukin-7 (IL-7),
IL-15, IL-23, IL-25 and IL-33. These signals induce the expression of transcription factors that promote the differentiation
of the various ILC subsets (group 1, 2 and 3 ILCs) and induce their expression of signature cytokines. The cytokines
secreted by ILCs promote important physiological responses, such as wound healing, tumour surveillance and protection
against infections. However, ILC-derived cytokines can also promote immunopathology in diseases such as asthma
and inflammatory bowel diseases (IBDs). AHR, aryl hydrocarbon receptor; E4BP4, E4 promoter-binding protein 4
(also known as NFIL3); GATA3, GATA-binding protein3; IFN, interferon-; I
H
2, innate helper2; LTi, lymphoid tissue-inducer;
NHC, natural helper cell; NK, natural killer; ROR, retinoic acid receptor-related orphan receptor.
REVI EWS
Common lymphoid
progenitor
(CLP). CLPs are the earliest
progenitors of the lymphoid
cell lineages, which include
Bcells, Tcells, NK cells and
the newly described innate
lymphoid cells. Bone marrow
CLPs are defined by their
expression of the IL-7 receptor,
FMS-related tyrosine kinase3
(FLT3) and KIT, and the
absence of all conventional
lineage markers.
Notch signalling
The Notch signalling
pathway regulates cellular
differentiation in various
tissues and at various stages
of development. During
lymphopoiesis, signals through
the Notch receptor modify
gene expression patterns and
have crucial roles in the
development of Tcells
and the inhibition of Bcell
differentiation. In mammals,
there are four Notch receptors,
which bind to ligands of the
Delta family (Delta-like 1,
Delta-like 3 and Delta-like 4)
and the jagged family (jagged 1
and jagged 2), which are
typically expressed on
stromal cells.
Aryl hydrocarbon receptor
(AHR). AHR is a cytosolic,
ligand-dependent transcription
factor that translocates to the
nucleus following the binding
of specific ligands, which
include dietary and microbial
metabolites. AHR participates
in the differentiation of
regulatory Tcells, T
H
17 cells
and intraepithelial intestinal
Tcells, and it is required for
the secretion of IL-22 by T
H
17
cells. More recently, AHR has
been shown to have crucial
roles in the development and
function of LTi cells and ILC3s.
LTi cells have been linked to the maintenance of Tcell
memory
38
, and the production of IL-17A and IL-22
by LTi cells has been shown to mediate immunity to
enteric pathogens
39,40
.
Following the first description of LTi cells in mice, a
recent report made a strong case for the existence of a
population of LIN
IL-7R
hi
CD45
int
RORt
+
LTi cells in
mesenteries isolated from 89week human embryos and
in mesenteric lymph nodes from second trimester (13
22week) human embryos
30
. These cells also expressed
transcripts encoding LT, LT and the transcription fac-
tor ID2, all of which are known to have roles in LTi cell
function and development. Although it is surprising that
these cells lacked CD4 expression, both CD4
+
and CD4

LTi cells do occur in mice, possibly indicating that there
is diversity in LTi cell phenotypes. Importantly, human
LIN
IL-7R
hi
CD45
int
RORt
+
LTi cells were capable of
inducing the expression of the adhesion molecules vas-
cular cell adhesion molecule1 (VCAM1) and intercel-
lular adhesion molecule1 (ICAM1) on mesenchymal
cells by producing lymphotoxin and TNF. The human
LTi cells also expressed transcripts encoding IL-22 and
IL-17A, suggesting that, similarly to mouse LTi cells,
they may promote protective immunity during infection.
ILC lineage relationships and plasticity
Studies of gene-targeted mice have provided a greater
understanding of the transcription factors that are
required to instruct the development of the various ILC
lineages (TABLE2). However, we currently lack a com-
plete appreciation of the temporal regulation of these
transcriptional changes and of the extrinsic signals that
are required for their induction. Furthermore, there is
considerable controversy regarding the developmental
relationships between the various ILC subsets and the
degree of plasticity that exists within each lineage and
permits the modification of its signature cytokine pro-
file. In this regard, it remains to be determined whether
ILC subset plasticity exists, akin to that observed among
Tcell subsets
41
.
A common ILC precursor? The various branches of the
ILC family share a series of commonalities, which allude
to a common ancestry and interrelated developmental
pathways. ILCs are of lymphoid origin, and cell-transfer
experiments have demonstrated that ILC2s and NK cells
arise from a common lymphoid progenitor (CLP; LIN
IL7R
+
FLT3
+
SCA1
low
KIT
low
), which in turn originates
from either the fetal liver or adult bone marrow
19,4245
.
It remains to be determined whether the ILC popula-
tions derived from fetal and adult haematopoiesis are
truly equivalent. With the exception of conventional NK
cells, all ILCs require IL-7 signalling for survival under
homeostatic conditions, and Notch signalling has also been
implicated in the development of the various ILC popu-
lations invitro
19,46,47
. Notably, ILCs share a requirement
for the transcriptional repressor ID2 (REFS10,27,46,48),
which inhibits the activity of the Eprotein transcription
factors and is likely to antagonize B and Tcell fates dur-
ing ILC development
49
. These shared signalling require-
ments and reliance on ID2 suggested that ILCs might
be derived from a common ID2-dependent pro genitor
that is directed towards particular ILC phenotypes by
the expression of lineage-specific transcription fac-
tors
50
. However, recent studies aimed at examining the
develop mental relationships between the ILC lineages
have indicated that additional complexity and plasticity
exist within this arm of haematopoiesis (FIG.2), the salient
features of which are discussedbelow.
The origin of group 3 ILCs. A close relationship between
the LTi cell and ILC3 lineages is suggested by their
shared requirement for several transcription factors,
such as ID2, RORt and the aryl hydrocarbon recep-
tor (AHR)
2427,35,48,5153
. However, it is currently unclear
whether LTi cells differentiate to acquire an ILC3 pheno-
type or whether these two ILC subsets represent distinct
lineages. Adoptive-transfer studies lend support to the
hypothesis that LTi cells are precursors to the ILC3 lin-
eage, as the transfer of lymph node or intestinal LTi cells
gives rise to NKp46
+
cells in the intestinal lamina propria
of alymphoid recipients
28
. However, consistent with the
alternative hypothesis, that ILC3s are a distinct develop-
mental lineage, it was reported that ILC3s originate from
CLP-like (LIN
SCA1
int
KIT
low
IL7R
+
) 47 integrin-
negative fetal liver precursors, which are distinct from the
ID2-expressing 47
+
cells that give rise to the LTi cell,
Tcell, NK cell and dendritic cell lineages
42,45
. Two addi-
tional studies have recently corroborated these findings,
and these studies also examined the role of Notch sig-
nalling in specifying the fate of RORt
+
ILCs. Although
the Notch signalling requirements may differ between
fetal and adult CLPs, both studies concluded that Notch
signals promote the generation of the 47
+
precursor,
but subsequently inhibit the upregulation of RORt and
the generation of LTi cells
46,47
. By contrast, the 47
pre-
cursor that gives rise to ILC3s does not require Notch
or ID2 for its generation (although subsequent stages of
ILC3 development do require these factors
52
). Thus, the
ancestry of ILC3s remains a contentious issue, and there
may be multiple routes by which these cells can be gener-
ated invivo. For example, whereas Notch signals promote
the generation of 47
+
precursors, a Notch-independent
route might also exist in fetal haematopoiesis
47
.
There are currently very few studies addressing the
role of Notch signalling in the development of group3
ILCs invivo. Conditional deletion of the gene encod-
ing recombining binding protein suppressor of hairless
(RBPJ) which is an essential mediator of Notch signal-
ling in haematopoietic cells resulted in fewer NKp46
+

ILCs in the intestinal lamina propria, but led to a lesser
reduction in the numbers of LTi cells
52
. Interestingly,
AHR signals have been shown to induce the expression
of Notch1 and Notch2 in ILC3s
52
, perhaps providing a
means to modulate this signalling pathway invivo.
Plasticity ILC3 to ILC1 transition? ILC3s display no
cytotoxic activity and secrete IL-22 rather than typical
NK cell cytokines such as IFN
2426
. However, it was
recently reported that a proportion of ILC3s (which were
fate-mapped for prior expression of RORt) downregu-
late RORt and acquire the capacity to produceIFN in
REVI EWS
REVI EWS
response to IL-12 and IL-23 (REF.28), although this find-
ing awaits confirmation. Similar plasticity exists within
the human ILC3 population, which when cultured with
IL-7 plus IL-2 expressed increased levels of IFN in
response to IL-23 stimulation, despite retaining RORt
expression
54,55
. The resulting cells, which were analogous
in phenotype to ILC1s, were potent inducers of disease
in a colitis model in which Rag2
/
mice were dosed sys-
temically with CD40-specific antibodies
28
, and they prob-
ably correspond to the RORt-dependent colitogenic
ILCs that were identified by another group
56
. The factors
determining the stability of RORt expression are poorly
understood, but IL-7 has been identified as a key determi-
nant in the maintenance of the ILC3 phenotype
28
. Indeed,
RORt
+
ILCs that were transferred to IL-7-transgenic
recipients maintained RORt expression, whereas the
expression of RORt was lost when these cells were
transferred to recipients receiving IL-7-specific blocking
antibodies
28
. Interestingly, RORt expression is reported
to be more stable in ILCs isolated from the small intestine
than in ILCs isolated from the colon, spleen or lymph
nodes
28,45,57
, suggesting that the stability of RORt is organ
specific and influenced by environmental factors, such as
diet and the commensal microbiota. Consistent with this,
commensal flora were shown to promote the production
of IL-7 by intestinal epithelial cells, and this correlated
with increased stability of the RORt
+
ILC population.
Furthermore, the transcription factor AHR, which
Table 2 | Signals and transcription factors that specify ILC lineages
Transcription
factor
Associated
ILC lineage
Consequence of deletion Proposed function Role in other lineages Refs
ID2 NK cells,
LTi cells,
ILC2s, ILC3s
All ILC lineages absent Antagonism of E protein
activity; suppression of B and
Tcell differentiation
Required for CD8
+
and CD103
+

dendritic cell lineages
10,27,
48,49,
100
E4BP4 NK cells Failure to develop conventional NK
cells
Induction of ID2? (In the
absence of E4BP4, a block in
development occurs prior to
ID2 expression; this defect is
partially restored by ectopic
expression of ID2)
Currently untested; lymph
node development is normal in
animals lacking E4BP4
101,102
ROR ILC2s Failure of ILC2 populations to
develop and/or expand in response
to IL-25 or IL-33
Regulator of development
and proliferation or survival;
specific gene targets remain
to be identified
Required, in conjunction
with RORt, for T
H
17 cell
development and IL-17
production; mice lacking ROR
have normal NK cell and ILC3
frequencies, and normal lymph
node development
18,19,
103
GATA3 NK cells,
ILC2s
Lack of thymic NK cell development
and IFN production by
conventional NK cells; conditional
deletion in ILC2s results in defective
development and IL-13 production
Required for NK cell
maturation
Crucial for Tcell development
and polarization to a T
H
2
phenotype; its role in
RORt-dependent ILCs is
untested
20,21,
58,104
RORt LTi cells,
ILC3s
Absence of LTi cells and ILC3s; failure
to develop lymph nodes, Peyers
patches, cryptopatches and ILFs
Regulator of development
and proliferation or survival;
specific gene targets remain
to be identified
Crucial for the development of
T
H
17 cells, Tcells and some
invariant NKT cells
2426,
35
AHR LTi cells,
ILC3s
Embryonically imprinted lymphoid
structures (for example, lymph nodes
and Peyers patches) are intact,
but postnatal lymphoid tissues (for
example, cryptopatches and ILFs) are
severely diminished; ILC3s are absent
Required for the proliferation
and maintenance of RORt
+

ILCs
Promotes the expansion of T
H
17
and Tcell populations and
their production of IL-22
5153,
105
TOX NK cells,
LTi cells
Impaired NK cell development;
reduced frequency of fetal and adult
LTi cells
ID2 expression is reduced
in Tox
/
NK cells, but the
developmental defect is
not restored by ectopic ID2
expression; specific roles in
LTi cells are unknown
Required at several stages
of Tcell development;
NKp46
+
RORt
+
CD3
cells are
present in the intestine of Tox
/

mice, suggesting that ILC3s may
develop independently of TOX;
its role in ILC2s is untested
106
RUNX proteins NK cells,
LTi cells
Impairment of NK cell maturation
(especially in the absence of RUNX3)
and LTi cell development
Required for the expression
of CD122 (the common
-subunit of the IL-2 and
IL-15 receptors); required for
the generation of 47
+
CLPs
Required for the differentiation
of multiple lineages, including
Tcells; required for 47
+
CLP
development, suggesting a role
in other ILC populations
107,108
AHR, aryl hydrocarbon receptor; CLP, common lymphoid progenitor; E4BP4, E4 promoter-binding protein4; GATA3, GATA-binding protein 3; ID2, inhibitor of DNA
binding 2; IL, interleukin; ILC, innate lymphoid cell; ILF, isolated lymphoid follicle; LTi, lymphoid tissue-inducer; NK, natural killer; ROR, retinoic acid receptor-related
orphan receptor; RUNX, RUNT-related transcription factor; T
H
, Thelper; TOX, thymocyte selection-associated high-mobility group box protein.
REVI EWS
HSC
CLP
B cell
T cell
NK cell
ILC2
LTi cell
ILC1
ILC3
IL-7
T-bet?
Loss of
RORt
Notch
ID2
RORt
Notch
ID2
Notch
GATA3
RORt Notch
E4BP4
Notch
ROR
GATA3
47
+
precursor
47
CLP
Notch
independent?
Forkhead box N1
(FOXN1). A winged-helix
transcription factor that is
thought to regulate keratin
gene expression. Mutations in
the Foxn1 gene result in a
hairless (nude) phenotype and
athymia.
binds to dietary and microbial metabolites, is reported
to influence the homeostasis of RORt-dependent ILC
populations
5153
. Thus, ILC3s retain the plasticity to divert
to an ILC1 phenotype, and their stability appears to be
regulated by specific environmental cues.
Development of ILC2s. Similarly to the other innate
lymphoid lineages, ILC2s are dependent on the trans-
cription factor ID2 (REF.10) and, at least invitro, require
Notch signals for their generation
19
. In the presence
of IL-7 and IL-33, ILC2s can be derived from double-
negative1 (DN1) and DN2 thymic precursors invitro
19
,
and it seems likely that, similarly to Tcells and NK cells,
the ILC2 lin eage might diverge from an ID2
+
47
+
pre-
cursor. However, given that ILC2s continue to develop in
athymic mice, it is probable that they can complete their
development in the bone marrow invivo
19
. Consistent
with this, CLPs can be differentiated invitro into ILC2s
by culturing them on OP9DL1 stromal cells
19
. This sys-
tem, in conjunction with adoptive cell transfers, has also
been used to identify a committed LIN
ILC2 precursor,
which is characterized by the expression of GATA3, ID2
and stem cell antigen1 (SCA1)
20
. ILC2s require the trans-
cription factor ROR, the expression of which appears to
be instrumental in driving the phenotype of these cells
18,19
.
Similarly, GATA3 has been shown recently to facilitate the
secretion of IL-13 by ILC2s
58
and, analogously to its role in
the development of T
H
2cells, this transcription factor has
a key role in promoting ILC2 development
20,21
. A minor
role has also been identified for signal transducer and
activator of transcription6 (STAT6) in promoting the
expansion of ILC2 populations following infection by
parasitic worms
58
. To date, there is no report of ILC2s
converting to any of the other ILC subsets.
ILCs: an evolutionary perspective
The evolutionary origin of ILCs is as yet unexplored,
although their relationship to Tcells is an interesting one.
Current evolutionary models of the adaptive immune
system show that Tcells capable of V(D)J rearrange-
ment first arose in jawed vertebrates that evolved 450
million years ago
59
. In addition, T-like cells that use gene
conversion to generate a diverse receptor repertoire
60,61

have been identified in jawless fish (which evolved ~500
million years ago). Jawless fish also possess a thymus-
like structure that expresses a forkhead box N1 (FOXN1)
orthologue and a network of Notch and Delta-like
proteins
62
. The existence of these two gene rearrange-
ment systems in lymphocytes suggests that these dis-
tinct populations may have developed from a common
ancestral ILC. Thus, the recent discovery of an extended
family of specialized ILCs raises the question of whether
an ILC was the primordial Tcell precursor.
LTi cells and ILC2s develop independently of the
thymus in Foxn1-null mice
19,63
and may therefore
pre-date the existence of this structure. Similarly to
modern-day ILCs, primordial ILCs might have had the
capability to orchestrate immune responses via cytokine
secretion, but lacked the ability to respond to specific
antigens. The IL-17 family of cytokines is important
for the functions of ILC2s and ILC3s, and homologues
of these cytokines have been described in sea urchins,
sea squirts and oysters. Two new homologues that
are phylogenetically related to Il17c and Il17d were
described recently in Oncorhynchus mykiss (rainbow
trout)
64
. Furthermore, the lamprey homologue of IL-17
is expressed by basal-layer epithelial cells in the lamprey
skin and is upregulated in response to lipopolysaccha-
ride stimulation
65
. However, the cytokine gene families
that characterize mammalian ILCs were largely absent
before the evolution of jawed fish
66
. Nonetheless, an
Il4 or Il13 orthologue has been identified in Tetraodon
nigroviridis (green spotted pufferfish) based on linkage
to the Rad50 gene
66
. Similarly, Il22 has been found in the
Danio rerio (zebrafish) genome clustered with Il26 and
Ifng, as it is in mammals
67
.
Figure 2 | A model for ILC development. Following the receipt of Notch signals,
common lymphoid progenitors (CLPs) in the bone marrow or fetal liver undergo
transcriptional changes that restrict their developmental potential to the Tcell, natural
killer (NK) cell, group 2 innate lymphoid cell (ILC) and lymphoid tissue-inducer (LTi) cell
lineages. These changes coincide with the expression of ID2 and 47 integrin. Further
ILC differentiation requires the expression of lineage-specific transcription factors, such
as retinoic acid receptor-related orphan receptor- (ROR), RORt or E4 promoter-
binding protein 4 (E4BP4), and is regulated by the availability of Notch signals. ILC3s are
reported to be derived from 47
CLPs and require Notch signals and ID2 expression for

full maturation, but they also arise from LTi cells in the periphery. In turn, ILC3s may lose
RORt expression in the absence of stabilizing signals such as interleukin-7 (IL-7)
and give rise to interferon- (IFN)-producing ILC1s. GATA3, GATA-binding protein3;
HSC, haematopoietic stem cell.
REVI EWS
REVI EWS
REG family of C-type lectins
Members of the REG3
subgroup of the C-type lectin
family are antimicrobial
peptides that interact with the
peptidoglycans present on the
surface of Gram-positive
bacteria. They can be released
into the intestinal lumen from
multiple epithelial cell lineages.
The major transcription factors responsible for ILC
development ROR
6,2426
and ROR
19
have not
been reported in organisms lower than vertebrates.
However, related retinoic acid receptors are evolution-
arily ancient and are found in Drosophila melanogaster,
Caenorhabditis elegans and Danio rerio
68
. The evolu-
tionary origins of ILCs are therefore unclear, but with
the identification of additional factors involved in ILC
development the field will be better placed to exam-
ine the contribution of ILCs to lymphocyte evolution.
Examination of lower vertebrates for the existence
of ILCs will help to refine our understanding of the
evolution of these newly definedcells.
ILC functions in infection
The existence of different ILC populations that can rapidly
secrete immunoregulatory cytokines suggests that these
cells may have evolved to provide immunity to infections.
Indeed, it is notable that ILC subsets seem to be particu-
larly prevalent at mucosal surfaces, which are constantly
exposed to infectious agents in the external environment.
The following sections discuss the growing evidence that
ILCs contribute to immune responses to infection and,
although the present focus is on their described roles
in the intestine, it is likely that future investigations will
unearth more diverse roles in other tissues.
ILCs in protective immunity to helminths. Type2 immu-
nity probably evolved to combat intestinal worm infec-
tions. Indeed, IL-13 is indispensible for the efficient
expulsion of the helminth parasite Nippostrongylus
brasiliensis, as this cytokine upregulates crucial physio-
logical responses, such as goblet cell mucus secretion
and the contraction of intestinal smooth muscle
69,70
.
Although Tcells are also essential for the expulsion of
helminth worms
71,72
, it was shown that Tcells are not the
crucial source of IL-13, as N.brasiliensis was expelled
from Rag2
/
mice reconstituted with CD4
+
Tcells from
Il4
/
Il13
/
mice
73
. Furthermore, wild-type CD4
+
Tcells
were incapable of inducing worm expulsion when trans-
ferred into Rag2
/
mice that were deficient in IL-4 and
IL-13. Thus, the essential source of IL-13 required for
the expulsion of N.brasiliensis must originate from the
innate immunesystem.
The first reported role for ILC2s in protective
immunity was in the response of IL-25-deficient mice
to N.brasiliensis infection
9
(FIG.3). The relevant ILC2
population was characterized as LIN
KIT
+
THY1.2
+
IL-13
+
IL-5
+
, and subsequent investigation using
Il13-EGFP reporter mice infected with N.brasiliensis
showed that these LIN
cells were the major source of

early IL-13 production, before the initiation of Tcell
responses. These ILC2s were readily detected in the
spleen, mesenteric lymph nodes, peritoneal cavity,
lungs and blood following exogenous administration of
IL-25, and their population expansion correlated with
increased worm clearance.
The adoptive transfer of ILC2s into N.brasiliensis-
infected Il17rb
/
Il1rl1
/
mice which are deficient in
IL-25 and IL-33 signalling and therefore severely impaired
in their ability to expel worms resulted in efficient
parasite elimination
11
. Moreover, the role of ILC2s as a
crucial source of IL-13 was demonstrated by the adop-
tive transfer of Il13
/
ILC2s, which failed to elicit worm
expulsion. Finally, transferring wild-type ILC2s into
IL-13-deficient mice confirmed that IL-13 secretion
from ILC2s alone is sufficient for worm expulsion
11
.
Worm expulsion coincided with goblet cell hyperplasia
and mucus production, which were also consequences
of the adoptive transfer of ILC2s into Il2rg
/
Rag2
/
mice
infected with N.brasiliensis
10,12
. It has been suggested that
the IL-25 required for worm expulsion is derived from the
epithelium and may amplify its own expression through
paracrine or autocrine feedback
74
.
A recent study also used helminth infection to inves-
tigate the potential roles of ILC2-expressed transcrip-
tion factors in protective immunity. GATA3 is expressed
by all ILC2s, and intracellular staining demonstrated
that GATA3
hi
ILC2s express IL-13 (REF.58). By cross-
ing Il13-Cre mice with Gata3
flox/flox
mice, this study also
revealed that GATA3-regulated IL-13 expression is cru-
cial for worm expulsion, but the relative contributions of
Tcells and ILCs could not be determined.
To date, there are limited reports on the roles of ILC2s
in other parasitic worm infections, and it will be of inter-
est to determine whether specific parasites have evolved
mechanisms to evade ILC2 activities.
ILCs in responses to enteric pathogens and commensals.
The intestinal immune system comprises a complex
array of lymphocytes, which are distributed throughout
the lamina propria and intraepithelial layer and are also
arranged in specific structures such as Peyers patches
(FIG.3) and cryptopatches. Peyers patches and crypto-
patches recruit other cells of the immune system, par-
ticularly Bcells, to counteract microbial invasion. In this
environment, there is a precarious equilibrium between
the intestinal immune system and the estimated 1 10
14

microbial symbionts that make up the mammalian
microbiota. Cytokine expression and regulation con-
tribute to this balance, with IL-17A and IL-22 having
keyroles.
Both IL-17A and IL-22 are crucial for the immune
response against enteric bacterial pathogens such as
Citrobacter rodentium, which causes acute colitis in
mice (FIG.3). IL-22 is upregulated early in the response
to C.rodentium, and neutralization of IL-22 during this
early phase, but not later in infection, results in increased
mortality
75
. This is due in part to IL-22 regulating the
secretion of antimicrobial proteins, such as those of
the REG family of C-type lectins, from epithelial cells
75
.
Importantly, IL-22 also has multiple roles in the main-
tenance of epithelial cell integrity and thus prevents the
dissemination of pathogenic bacteria
76
.
Studies of Rag2
/
mice demonstrated that, in the early
phase of C.rodentium infection, IL-22 is produced from
an innate cell source. Furthermore, Rag2
/
mice were
shown to eventually die as a result of chronic inflamma-
tion, rather than as a result of a failure to maintain epi-
thelial integrity and contain the infection
77
. The innate
IL-22-producing cell population was originally proposed
to comprise dendritic cells
75
, but recently it has been
REVI EWS
Peyers
patch
Parasitic
helminth
Microorganism
IL-6
ILC2s
IL-13 IL-5
B cells
Goblet cell
hyperplasia
Mucus
hypersecretion
Homeostasis
Response to
bacterial infection
Microbiota
Helicobacter Citrobacter
Defensins and
antibacterial
peptides
IL-22
B1 cells
Antibodies
IL-25
?
IL-22
NCR
ILC3s
NCR
+
ILC3s
Intestinal
epithelial cell
Intestinal lumen
Goblet cell
Allergen
Mucus layer
Mucus layer
IL-17
IL-23
IL-17
IL-13
IL-13
IL-13
?
IL-5
IL-4, IL-5,
IL-9, IL-13
IL-5,
IL-6
IL-4
?
T
H
2 cells
IL-25,
IL-33
IL-25,
IL-33
IL-22
ILC3
ILC2s
DC
b a
c
Lymphotoxin and
TNF for development
of Peyers patch
LTi cells
Eosinophil
Alternatively
activated
macrophage
Smooth
muscle
cell
MHC class II
antigen
presentation
Amphiregulin
promotes
wound repair
Smooth muscle
contraction
Undened
interaction and
maintenance factors
Fibrosis
Parasitic
helminth
demonstrated that ILC3s are the predominant source of
IL-22 during C.rodentium infection
52
. In fact, the pheno-
type of the originally reported protective dendritic cell
(CD11c
+
LY49B
) is consistent with that of anILC3.

Mice lacking the NKp46
+
and NKp46
ILC3 sub-
sets
26,40
(owing either to AHR deficiency
52
or to combined
RAG2 and
c
deficiency
26
) fail to contain C.rodentium
infection in the gut. Similarly to the phenotype of Il22
/

mice, the intestines of infected AHR-deficient mice
exhibit an increased infiltration of inflammatory cells,
mucosal hyperplasia and erosion of the epithelium
52,75
.
Analogously to their role in the response to bac-
terial pathogens, ILC3s also provide an early source
of IL-22 during Candida albicans fungal infection
78
,
and a recent study indicated that they promote the
anatomical containment of lymphoid tissue-resident
commensal bacteria
79
. ILC3s therefore provide a rapid
source of IL-22 to strengthen the epithelial barrier in
response to epithelial stress or breach. However, cells
of the adaptive immune system (probably T
H
1 and
T
H
17 cells) are still required to completely eliminate
infection. This rapid innate response is indicative of
Figure 3 | Schematic of the roles for ILCs in
intestinal immune function. a | Innate lymphoid cells
(ILCs) have various immune functions in the intestine.
Lymphoid tissue-inducer (LTi) cells express lymphotoxin
and tumour necrosis factor (TNF), thereby upregulating
the expression of adhesion molecules on the epithelium
and inducing the development of lymphoid tissues, such
as Peyers patches. Peyers patches harbour ILC2s that
can provide interleukin-5 (IL-5), IL-6 and IL-13 to Bcells.
b|ILC3-mediated production of IL-22 maintains
homeostasis with the intestinal microbiota and is
modulated by dendritic cells (DCs), which are in turn
regulated by IL-25 released by the epithelium. During
bacterial infection, IL-22 expression is elevated
following termination of the IL-25 signal, resulting
in the increased release of antimicrobial peptides and
defensins. c|Parasitic worm infection results in the
release of IL-25 and IL-33 from epithelial cells. These
factors induce the proliferation of ILC2s and their
expression of IL-5, IL-6, IL-13 and possibly IL-4. These
cytokines in turn drive type2 effector responses, including
mucus hypersecretion, the alternative activation of
macrophages, eosinophilia and Bcell proliferation.
A question mark denotes suspected pathways that
have not been proven formally. T
H
2,Thelper2.
REVI EWS
REVI EWS
Amphiregulin
A member of the epidermal
growth factor family that drives
the proliferation of epithelial
cells and fibroblasts to
promote tissue repair and
remodelling in response to
epithelial injury.
crosstalk between ILCs and epithelial cells, which is
echoed in the response to helminths. The nature of these
signals is not well understood but clearly requires epithe-
lial cells to sense microbial products (possibly indirectly)
and to release factors that promote the appropriate ILC
response.
ILCs in asthma and allergy
In addition to the crucial roles identified for ILCs in
response to pathogens, recent studies have highlighted
the involvement of ILC subsets in regulating tissue
homeostasis and pathology. Allergic responses are
characterized by the production of type2 cytokines,
leading to eosinophil and mast cell degranulation,
goblet cell hyperplasia, mucus production, increased
serum IgE levels and smooth muscle contraction. Such
responses can develop following repeated low-dose
exposure to normally innocuous allergens, such as
bacterial products, food items, plant pollens or fungal
spores at mucosal barriers.
The preconception that allergic lung responses are
solely T
H
2 cell-mediated is now being questioned fol-
lowing the discovery of ILC2s. Although T
H
2 cells are a
major source of type2 cytokines during allergic asthma,
ILC2s also contribute to disease pathology. Using a com-
pound mouse strain expressing EGFP as a reporter for
IL-4 and the fluorescent protein tdTomato as a reporter
for IL-13, T
H
2 cells were identified as the major cellu-
lar source of these cytokines in an ovalbumin-induced
mouse model of allergic lung inflammation
13,80
. Strikingly,
however, ILC2s also expressed Il13-tdTomato but not
Il4-EGFP. Taken together, T
H
2 cells and ILC2s accounted
for the majority of IL-13 expression in the lungs during
ovalbumin-induced lung allergy. ILC2s also accounted for
the majority of IL-13 expression in the lungs in response
to both IL-25 and IL-33 (REFS13,16,80), and they have
subsequently been shown to express IL-5 (in Il5-Venus
reporter mice) and to respond to thymic stromal
lymphopoietin (TSLP), in synergy with IL-33, invitro
81,82
.
In studies using Il13
/
mice, which are refractory
to the induction of allergic lung inflammation, it was
shown that the transfer of IL-13-expressing ILC2s was
sufficient to restore airway hyperreactivity, eosino-
philia and cytokine production in an IL-25-induced
lung inflammation model (REF.13 and J.L.B., unpub-
lished observations). ILC2s were also sufficient to drive
allergic responses in glycolipid-induced lung allergy
16
.
Therefore, IL-13 production by ILC2s alone can restore
allergic responses, even when IL-13 from CD4
+
Tcells
is absent. Similarly, intranasal treatment of mice with
a fungal allergen from Alternaria alternata also led to
increased production of the ILC2-inducing cytokine
IL-33. Maximal IL-33 production occurred at ~12 hrs
after treatment and resulted in IL-33R-dependent ILC2
population expansion in the lungs, eosinophilia and
IL-5 and IL-13 production
14
.
The important role of ILC2s in virus-induced experi-
mental models of airway hyperreactivity has been rec-
ognized recently. Several viral respiratory infections
(namely rhinovirus, respiratory syncytial virus and
influenza virus infections) promote type2 responses
and exacerbate allergic asthma
83
. However, the mecha-
nisms by which this occurs are unclear. One group
demonstrated that infection of mice with influenza A
virus (strain H3N1) caused airway hyperreactivity in
an IL-33R- and IL-13-dependent manner that was inde-
pendent of B and Tcells
15
. The development of H3N1
influenza A virus-induced airway hyperreactivity was
preceded by the production of IL-33 by alveolar macro-
phages and increased numbers of ILC2s in the lungs.
Treatment of mice with THY1-specific depleting anti-
bodies to remove ILC2 populations (THY1 is expressed
by all ILCs, but also by basophils and numerous other
cell types) resulted in resistance to virus-induced airway
hyperreactivity. By contrast, the transfer of ILC2s into
Il13
/
mice which are normally resistant to virus-
induced airway hyperreactivity resulted in the devel-
opment of airway hyperreactivity in the mice following
virus infection
15
. Similar results were reported by another
group, who went on to show that amphiregulin is expressed
by ILC2s during viral lung infection, and it was suggested
that this is important for tissue repair
17
.
Given the recent identification of human ILC2s in
samples from patients with chronic rhinosinusitis
23
, it is
important that future studies investigate the role of these
cells in other allergic disorders, such as atopic dermati-
tis and allergic asthma. Furthermore, studies of influ-
enza virus infection in mice highlight potential roles for
ILC2s in virus-induced asthma exacerbation
15,17
.
ILCs in inflammatory bowel diseases
Inflammatory bowel diseases (IBDs), such as Crohns
disease and ulcerative colitis, are chronic inflammatory
disorders of the gastrointestinal tract. Crohns disease
is characterized by transmural, discontinuous inflam-
mation along the intestinal tract, whereas ulcerative
colitis involves inflammation of the superficial mucosal
and submucosal tissue layers of the colon. These dis-
eases have a highly complex aetiology that may include
mutations in single crucial genes or in a combination
of multiple disease susceptibility alleles. These genetic
aberrations lead to the disruption of intestinal homeo-
stasis, including effects on epithelial barrier function,
local immune cell responses and the diversity of the gut
microbiota
84
.
IL-17A, IL-17F, IL-22 and IFN have essential roles
in IBDs
84
, whereas IL-13 has been reported to play a sig-
nificant part in ulcerative colitis
85,86
. Although the secre-
tion of IL-17A, IL-22 and IFN is principally ascribed
to T
H
cells, additional sources of these cytokines include
Tcells, natural killerT (NKT) cells and NK cells
84
.
Notably, recent studies have also implicated ILCs in the
development of IBDs. One group reported the exist-
ence of a CD11b
B220
GR1
THY1
+
ILC population
that arose in Rag2
/
mice in response to Helicobacter
hepaticus infection and that secreted IL-17A, IL-22 and
IFN in response to IL-23 (REF.56). A functional role for
these cells was determined by showing that antibody-
mediated depletion of THY1
+
cells in H. hepaticus-
infected Rag2
/
mice ameliorated disease development,
although once again the caveat remains that THY1 is not
specifically expressed byILCs.
REVI EWS
Adaptive lymphoid cells Innate lymphoid cells
GATA3
ROR
Notch
RORt
RORt
AHR
T-bet
RORt
RORt
E4BP4
?
ILC2
LTi cell
Group 2 ILCs
Group 3 ILCs
Group 1 ILCs
NCR
ILC3
NCR
+
ILC3
T
H
2
cell
T
H
17
cell
T
H
1
cell
T
H
22
cell
GATA3
ILC1
NK cell
Lymphoid
precursor
Similarly, abrogation of colitic pathology was
observed when THY1
+
ILCs were depleted in a mouse
model of colitis that is induced by the administration of
CD40-specific antibodies, and the decreased pathology
following ILC depletion coincided with decreased levels
of IFN, IL-22 and TNF
56
. The colitogenic ILCs did not
produce IL-17A, possibly indicating an element of plas-
ticity that is dependent on the specific stimuli. Although
these cells appear to be phenotypically distinct from the
IFN-producing NK receptor-expressing (NKR
+
) LTi
cell population that was previously shown to promote
colitis
28
, it is likely that such RORt
IFN
+
NKR
+
LTi
cells reside within this heterogenous THY1
+
SCA1
+

population
56
. Thus, ILCs can contribute to the devel-
opment of intestinal inflammation by secreting IL-17A
and IFN in response to IL-23. A role for ILCs has also
been demonstrated recently in the Tbx21
/
Rag2
/

ulcerative colitis (TRUC) disease model
87
. These mice
have a predominance of ILC3s secreting IL-17A, but
very few IFN-expressing cells, and treatment with a
THY1-specific antibody ameliorated disease.
ILCs may also maintain intestinal homeostasis dur-
ing colonization with the intestinal microbiota by pro-
moting the formation of isolated lymphoid follicles. In
the absence of RORt (which results in the loss of LTi
cells, isolated lymphoid follicles and T
H
17 cells), large
numbers of Bcell-rich tertiary lymphoid tissues form
in response to the natural endogenous load of intes-
tinal bacteria
88
. Following dextran-sulphate sodium
(DSS)-induced epithelial barrier damage, Rorc
/

mice develop severe intestinal inflammation charac-
terized by the infiltration of neutrophils and Bcells.
These pathological consequences were reversed by
antibiotic treatment or the administration of intra-
venous IgG. Thus, the depletion of RORt-dependent
cells which include LTi cells, ILC3s and T
H
17 cells
results in compromised homeostasis with the
intestinal microbiota.
ILCs have also been detected in the human intes-
tine and accumulate under the inflammatory condi-
tions that occur in Crohns disease
89
. In this study,
LIN
CD45
+
cells from the ileum and colon of patients
with Crohns disease were sorted on the basis of their
expression of CD56. The LIN
CD45
+
CD56
+
cells
could be induced to express mRNA encoding IL-22
and IL-26 in response to IL-23 stimulation, whereas
the LIN
CD45
+
CD56
cells expressed IL-17A and

IL-17F, and this was not altered by IL-23. IFN was
expressed by both subsets. Another study also detailed
distinct NKp44
+
and NKp46
+
ILC populations in the
intestines of patients with Crohns disease
90
. The
NKp44
+
NKp46
CD56
+
CD122
+
IL-7R
+
cells expressed
IL-22 (suggesting that they are a type of ILC3), and the
authors reported that the numbers of these cells were
decreased in patient samples compared with controls.
By contrast, the NKp44
NKp46
+
CD56
+
CD122
+
IL-7R

cells responded to IL-23 by secreting IFN, which is
consistent with an ILC1 phenotype, and the numbers
of these cells were increased in patients with Crohns
disease. It is clear from these reports that extensive
phenotyping is necessary to more accurately categorize
the ILC populations that are present in the inflamed
human intestine.
Unlike Crohns disease, ulcerative colitis is dis-
tinguished by a type2 immune phenotype, and the
levels of IL-4, IL-5 and IL-13 associate with the sever-
ity of intestinal pathology in patients
85,91
. Recently,
IL-13-producing ILC2s have been described in an
oxazolone-induced mouse model of colitis, which
is characterized by a type2 inflammatory response.
This correlated with the expansion of IL-13-producing
NKT cell populations, in keeping with previous
reports
86
. Notably, at the time points analysed, the
IL-13-secreting NKT cells were localized almost
entirely in the mesenteric lymph nodes, whereas the
ILC2s were distributed in the lamina propria of the
intestinal mucosa. This study also demonstrated that
neutralizing IL-25-specific and IL-17RB-specific
antibodies effectively blocked pathology in this
mouse model. Further investigations will be neces-
sary to elucidate the functional importance of ILC2s
in humanIBDs.
Figure 4 | Comparison of Thelper cell and ILC subsets. The innate lymphoid cell
(ILC) subsets (shown on the right) broadly parallel the known T helper (T
H
) cell subsets
(shown on the left) in terms of their signature cytokine secretion profiles. An
overlapping series of transcription factors is also used to drive the differentiation of
the various ILC and T
H
cell subsets. AHR, aryl hydrocarbon receptor; E4BP4, E4
promoter-binding protein 4; GATA3, GATA-binding protein3; I
H
2, innate helper2; LTi,
lymphoid tissue-inducer; NHC, natural helper cell; NK, natural killer; ROR, retinoic acid
receptor-related orphan receptor.
REVI EWS
REVI EWS
ILC crosstalk with other cells
An important question with regard to ILCs is how
these cells interact with other cells in their surround-
ing environment. Several studies suggest that epithelial
cell-derived factors, and signals from adaptive immune
cells, may be important for regulating ILCs. In the intes-
tine, it was noted that IL-25 levels, which were increased
by age and microbial colonisation, correlated inversely
with those of IL-22, and that exogenous administration
of IL-25 suppressed the expression of IL-22 by ILC3s
92
.
This effect was not direct and required an intermediary
IL-25-responsive dendritic cell population. Supporting
these findings, Il25
/
mice had more ILC3s. In the
lungs, IL-22 is required for the onset of airway inflam-
mation, but also has a protective effect during established
inflammation
93,94
. The predominant source of IL-22 in an
allergic asthma model was LIN
THY1.2
+
SCA1
+
RORt
+

ILC3s
95
, a proportion of which also produced IL-17A.
Interestingly, the abundance of IL-25 in bronchoalveolar
lavage fluid correlated inversely with the levels of IL-22,
and treatment with IL-25-specific blocking antibodies
was sufficient to reverse the pro-inflammatory effect
of IL-22-specific antibodies
95,96
. Thus, IL-22 and IL-25
have antagonistic roles in controlling immune responses
in mucosal tissues. There is also evidence that IL-17A
and IL-25 may interact to influence lung inflammation in
mice
97
. The ability of IL-25-specific antibodies to prevent
airway hyperreactivity is dependent on increased produc-
tion of IL-17A in the lungs, and simultaneous blockade of
IL-17A inhibits the therapeutic efficacy of IL-25-specific
treatment. In this model, IL-17A was shown to be derived
from an undefined non-Bcell and non-Tcell source
97
.
In addition to the crosstalk that exists between ILCs
and the epithelium, ILCs might also be influenced by the
adaptive immune system. During helminth infection
in Rag2
/
mice, it was noted that ILC2 numbers were
not maintained, suggesting that Tcells provide survival
signals to ILCs, for example through the production of
IL-2 (REFS11,98). Although it remains to be determined
whether ILC2s can process and present antigens, the
expression of MHC class II molecules by ILC2s indicates
that MHCTcell receptor interactions might facilitate
dialogue between these cell populations
11
. Physiologically,
this could provide a means for ILCs to contribute to the
initiation of a Tcell response through antigen presenta-
tion, and it suggests a mechanism for the termination of
the ILC response as the antigen is cleared and the Tcell
population contracts.
The future the known unknowns
Research over the past few years has revealed a previously
unappreciated family of ILCs with diverse physiological
roles, ranging from immune protection to wound repair
and homeostasis. Remarkable progress has been made
in this field, with the discovery not only of distinct sub-
sets of ILCs but also of the transcription factors that are
responsible for their development. Indeed, a comparison
of Tcell and ILC subsets now reveals striking similari-
ties (FIG.4). However, many challenges remain (BOX1), not
least the identification and more detailed characterization
of the roles of ILCs in human health and disease.
So, ILCs how did we miss them? Well, we had just
gated them out, assuming that we already knew all the
players. Who knows what other unknowns wait to be
discovered within the LIN
population?
Note added in proof
A recent report has indicated a central role for T-bet in
ILC3 development
109
.
Box 1 | Challenges facing the ILC field
The elucidation of the physiological roles of innate lymphoid cells (ILCs) in health and disease requires the development
of more sophisticated mouse models in which the various ILC lineages can be deleted specifically, rather than relying on
antibody-mediated depletion strategies that invariably result in collateral damage to other cell populations. Such mice
will also enable the distinct roles of ILCs and Tcells during immune responses and wound healing to be dissected, which
will in turn clarify the immunological significance of having these two, distinctly regulated sources of cytokines.
The current knowledge of the tissue localization of ILCs, their chemokine-regulated migration and their interactions with
other immune and stromal cells is in its infancy. Progress will be aided by the development of new cell-lineage-reporter mouse
strains to enable the marking of ILCs in the context of other adaptive and innate cell populations during immune responses.
Future investigations need to better define the interactions of ILCs with the adaptive immune system in order to
understand the initiation, maintenance and termination of immune responses. A role for regulatory ILC subsets in the
resolution phase of immune responses remains an unexplored possibility.
Despite significant progress in understanding the development of ILCs, investigation of the temporal regulation of
crucial transcription factors and the signals required to direct differentiation is lacking. Such studies may begin to
define the degrees of overlap and the subtle differences between ILC and Tcell development.
1. Spits, H. etal. Innate lymphoid cells a proposal
for uniform nomenclature. Nature Rev. Immunol.
7 Jan 2013 (doi:10.1038/nri3365).
2. Kiessling, R. Klein, E., Pross, H. & Wigzell, H. Natural
killer cells in the mouse. II. Cytotoxic cells with specificity
for mouse Moloney leukemia cells. Characteristics of the
killer cell. Eur. J.Immunol. 5, 117121 (1975).
3. Herberman, R.B., Nunn, M.E., Holden, H.T. &
Lavrin, D.H. Natural cytotoxic reactivity of mouse
lymphoid cells against syngeneic and allogeneic
tumors. II. Characterization of effector cells.
Int.J.Cancer. 16, 230239 (1975).
4. Vivier, E. etal. Innate or adaptive immunity? The
example of natural killer cells. Science 331, 4449
(2011).
5. Di Santo, J.P. & Vosshenrich, C.A. Bone marrow
versus thymic pathways of natural killer cell
development. Immunol. Rev. 214, 3546 (2006).
6. Crellin, N.K., Trifari, S., Kaplan, C.D., Cupedo, T. &
Spits, H. Human NKp44
+
IL-22
+
cells and LTi-like cells
constitute a stable RORC
+
lineage distinct from
conventional natural killer cells. J.Exp. Med. 207,
281290 (2010).
7. Hurst, S.D. etal. New IL-17 family members promote
Th1 or Th2 responses in the lung: in vivo function of
the novel cytokine IL-25. J.Immunol. 169, 443453
(2002).
8. Fort, M.M. etal. IL-25 induces IL-4, IL-5, and IL-13
and Th2-associated pathologies in vivo. Immunity 15,
985995 (2001).
REVI EWS
9. Fallon, P.G. etal. Identification of an interleukin
(IL)-25-dependent cell population that provides IL-4,
IL-5, and IL-13 at the onset of helminth expulsion.
J.Exp. Med. 203, 11051116 (2006).
10. Moro, K. etal. Innate production of T
H
2 cytokines by
adipose tissue-associated c-Kit
+
Sca-1
+
lymphoid cells.
Nature 463, 540544 (2010).
11. Neill, D.R. etal. Nuocytes represent a new innate
effector leukocyte that mediates type-2 immunity.
Nature 464, 13671370 (2010).
12. Price, A.E. etal. Systemically dispersed innate
IL-13-expressing cells in type 2 immunity. Proc. Natl
Acad. Sci. USA 107, 1148911494 (2010).
References 1012 comprehensively characterize the
group2 ILCs (referred to as nuocytes, NHCs and I
H
2
cells) that were first identified in references 79.
13. Barlow, J.L. etal. Innate IL-13-producing nuocytes
arise during allergic lung inflammation and contribute
to airways hyperreactivity. J.Allergy Clin. Immunol.
129, 191198 (2012).
14. Bartemes, K.R. etal. IL-33-responsive lineage
CD25
+
CD44
hi
lymphoid cells mediate innate type2
immunity and allergic inflammation in the lungs.
J.Immunol. 188, 15051513 (2011).
15. Chang, Y.J. etal. Innate lymphoid cells mediate
influenza-induced airway hyper-reactivity
independently of adaptive immunity. Nature Immunol.
12, 631638 (2011).
16. Kim, H.Y. etal. Innate lymphoid cells responding to
IL-33 mediate airway hyperreactivity independently of
adaptive immunity. J.Allergy Clin. Immunol. 129,
216227 (2012).
17. Monticelli, L.A. etal. Innate lymphoid cells promote
lung-tissue homeostasis after infection with influenza
virus. Nature Immunol. 12, 10451054 (2011).
18. Halim, T.Y. etal. Retinoic-acid-receptor-related
orphan nuclear receptor is required for natural
helper cell development and allergic inflammation.
Immunity 37, 463474 (2012).
19. Wong, S.H. etal. Transcription factor ROR is critical
for nuocyte development. Nature Immunol. 13,
229236 (2012).
References 18 and 19 illustrate the crucial role for
the transcription factor ROR in the development
of ILC2s.
20. Hoyler, T. etal. The transcription factor GATA-3
controls cell fate and maintenance of type 2 innate
lymphoid cells. Immunity 37, 634648 (2012).
21. Mjosberg, J. etal. The transcription factor GATA3 is
essential for the function of human type 2 innate
lymphoid cells. Immunity 37, 649659 (2012).
References 20 and 21 characterize the role of the
transcription factor GATA3 in ILC2 development in
mice and humans.
22. Barlow, J.L. & McKenzie, A.N. Nuocytes: expanding
the innate cell repertoire in type-2 immunity.
J.Leukoc. Biol. 90, 867874 (2011).
23. Mjosberg, J.M. etal. Human IL-25- and
IL-33-responsive type 2 innate lymphoid cells are
defined by expression of CRTH2 and CD161. Nature
Immunol. 12, 10551062 (2011).
This paper is the first description of ILC2s in
humans.
24. Luci, C. etal. Influence of the transcription factor
RORt on the development of NKp46
+
cell
populations in gut and skin. Nature Immunol. 10,
7582 (2009).
25. Sanos, S.L. etal. RORt and commensal microflora
are required for the differentiation of mucosal
interleukin 22-producing NKp46
+
cells. Nature
Immunol. 10, 8391 (2009).
26. Satoh-Takayama, N. etal. Microbial flora drives
interleukin 22 production in intestinal NKp46
+
cells
that provide innate mucosal immune defense.
Immunity 29, 958970 (2008).
References 2426 are the first reports of
intestinal lymphoid cells that express NKp46
but are distinct from NK cells and require the
transcription factor ROR for their development.
27. Satoh-Takayama, N. etal. IL-7 and IL-15
independently program the differentiation of
intestinal CD3
NKp46
+
cell subsets from
Id2-dependent precursors. J.Exp. Med. 207,
273280 (2010).
28. Vonarbourg, C. etal. Regulated expression of
nuclear receptor RORt confers distinct functional
fates to NK cell receptor-expressing RORt
+
innate
lymphocytes. Immunity 33, 736751 (2010).
29. Cella, M. etal. A human natural killer cell subset
provides an innate source of IL-22 for mucosal
immunity. Nature 457, 722725 (2009).
30. Cupedo, T. etal. Human fetal lymphoid tissue-inducer
cells are interleukin 17-producing precursors to
RORC
+
CD127
+
natural killer-like cells. Nature
Immunol. 10, 6674 (2009).
31. Hughes, T. etal. Stage 3 immature human natural
killer cells found in secondary lymphoid tissue
constitutively and selectively express the T
H
17
cytokine interleukin-22. Blood 113, 40084010
(2009).
32. Mebius, R.E., Rennert, P. & Weissman, I.L.
Developing lymph nodes collect CD4
+
CD3
LT
+
cells
that can differentiate to APC, NK cells, and follicular
cells but not T or B cells. Immunity 7, 493504
(1997).
33. Mebius, R.E., Streeter, P.R., Michie, S., Butcher, E.C.
& Weissman, I.L. A developmental switch in
lymphocyte homing receptor and endothelial vascular
addressin expression regulates lymphocyte homing
and permits CD4
+
CD3
cells to colonize lymph

nodes. Proc. Natl Acad. Sci. USA 93, 1101911024
(1996).
34. Yoshida, H. etal. IL-7 receptor
+
CD3
cells in the
embryonic intestine induces the organizing center of
Peyers patches. Int. Immunol. 11, 643655 (1999).
35. Eberl, G. etal. An essential function for the nuclear
receptor RORt in the generation of fetal lymphoid
tissue inducer cells. Nature Immunol. 5, 6473
(2004).
36. Eberl, G. & Littman, D.R. Thymic origin of intestinal
T cells revealed by fate mapping of RORt
+
cells.
Science 305, 248251 (2004).
37. Scandella, E. etal. Restoration of lymphoid organ
integrity through the interaction of lymphoid tissue-
inducer cells with stroma of the T cell zone.
Nature Immunol. 9, 667675 (2008).
38. Withers, D.R. etal. Cutting edge: lymphoid tissue
inducer cells maintain memory CD4 T cells within
secondary lymphoid tissue. J.Immunol. 189,
20942098 (2012).
39. Takatori, H. etal. Lymphoid tissue inducer-like cells
are an innate source of IL-17 and IL-22. J.Exp. Med.
206, 3541 (2009).
40. Sonnenberg, G.F., Monticelli, L.A., Elloso, M.M.,
Fouser, L.A. & Artis, D. CD4
+
lymphoid tissue-inducer
cells promote innate immunity in the gut. Immunity
34, 122134 (2011).
41. OShea, J.J. & Paul, W.E. Mechanisms underlying
lineage commitment and plasticity of helper CD4
+

Tcells. Science 327, 10981102 (2010).
42. Yoshida, H. etal. Expression of 47 integrin defines a
distinct pathway of lymphoid progenitors committed
to T cells, fetal intestinal lymphotoxin producer, NK,
and dendritic cells. J.Immunol. 167, 25112521
(2001).
43. Mebius, R.E. etal. The fetal liver counterpart of
adult common lymphoid progenitors gives rise to all
lymphoid lineages, CD45
+
CD4
+
CD3
cells, as well as
macrophages. J.Immunol. 166, 65936601 (2001).
44. Yang, Q., Saenz, S.A., Zlotoff, D.A., Artis, D. &
Bhandoola, A. Cutting edge: natural helper cells
derive from lymphoid progenitors. J.Immunol. 187,
55055509 (2011).
45. Sawa, S. etal. Lineage relationship analysis of RORt
+

innate lymphoid cells. Science 330, 665669 (2010).
46. Cherrier, M., Sawa, S. & Eberl, G. Notch, Id2, and
RORt sequentially orchestrate the fetal development
of lymphoid tissue inducer cells. J.Exp. Med. 209,
729740 (2012).
47. Possot, C. etal. Notch signaling is necessary for adult,
but not fetal, development of RORt
+
innate lymphoid
cells. Nature Immunol. 12, 949958 (2011).
48. Yokota, Y. etal. Development of peripheral lymphoid
organs and natural killer cells depends on the helix-
loop-helix inhibitor Id2. Nature 397, 702706
(1999).
49. Boos, M.D., Yokota, Y., Eberl, G. & Kee, B.L. Mature
natural killer cell and lymphoid tissue-inducing cell
development requires Id2-mediated suppression of
Eprotein activity. J.Exp. Med. 204, 11191130
(2007).
50. Spits, H. & Di Santo, J.P. The expanding family of
innate lymphoid cells: regulators and effectors of
immunity and tissue remodeling. Nature Immunol.
12, 2127 (2011).
51. Kiss, E.A. etal. Natural aryl hydrocarbon receptor
ligands control organogenesis of intestinal lymphoid
follicles. Science 334, 15611565 (2011).
52. Lee, J.S. etal. AHR drives the development of gut
ILC22 cells and postnatal lymphoid tissues via
pathways dependent on and independent of Notch.
Nature Immunol. 13, 144151 (2012).
53. Qiu, J. etal. The aryl hydrocarbon receptor regulates
gut immunity through modulation of innate lymphoid
cells. Immunity 36, 92104 (2012).
54. Cella, M., Otero, K. & Colonna, M. Expansion of
human NK-22 cells with IL-7, IL-2, and IL-1 reveals
intrinsic functional plasticity. Proc. Natl Acad. Sci. USA
107, 1096110966 (2010).
55. Hughes, T. etal. Interleukin-1 selectively expands
and sustains interleukin-22
+
immature human natural
killer cells in secondary lymphoid tissue. Immunity 32,
803814 (2010).
56. Buonocore, S. etal. Innate lymphoid cells drive
interleukin-23-dependent innate intestinal pathology.
Nature 464, 13711375 (2010).
This paper is the first description of ILCs in
inflammatory bowel disease models.
57. Vonarbourg, C. & Diefenbach, A. Multifaceted roles
of interleukin-7 signaling for the development and
function of innate lymphoid cells. Semin. Immunol.
24, 165174 (2012).
58. Liang, H.E. etal. Divergent expression patterns of
IL-4 and IL-13 define unique functions in allergic
immunity. Nature Immunol. 13, 5866 (2012).
59. Bajoghli, B. etal. Evolution of genetic networks
underlying the emergence of thymopoiesis in
vertebrates. Cell 138, 186197 (2009).
60. Alder, M.N. etal. Diversity and function of adaptive
immune receptors in a jawless vertebrate. Science
310, 19701973 (2005).
61. Pancer, Z. etal. Variable lymphocyte receptors in
hagfish. Proc. Natl Acad. Sci. USA 102, 92249229
(2005).
62. Bajoghli, B. etal. A thymus candidate in lampreys.
Nature 470, 9094 (2011).
63. Saito, H. etal. Generation of intestinal T cells from
progenitors residing in gut cryptopatches. Science
280, 275278 (1998).
64. Wang, T., Martin, S.A. & Secombes, C.J.
Two interleukin-17C-like genes exist in rainbow trout
Oncorhynchus mykiss that are differentially expressed
and modulated. Dev. Comp. Immunol. 34, 491500
(2010).
65. Tsutsui, S., Nakamura, O. & Watanabe, T. Lamprey
(Lethenteron japonicum) IL-17 upregulated by LPS-
stimulation in the skin cells. Immunogenetics 59,
873882 (2007).
66. Ohtani, M., Hayashi, N., Hashimoto, K., Nakanishi, T.
& Dijkstra, J.M. Comprehensive clarification of two
paralogous interleukin 4/13 loci in teleost fish.
Immunogenetics 60, 383397 (2008).
67. Lane, P.J., Gaspal, F.M., McConnell, F.M.,
Withers, D.R. & Anderson, G. Lymphoid tissue inducer
cells: pivotal cells in the evolution of CD4 immunity and
tolerance? Front. Immunol. 3, 24 (2012).
68. Flores, M.V., Hall, C., Jury, A., Crosier, K. & Crosier, P.
The zebrafish retinoid-related orphan receptor (ror)
gene family. Gene Expr. Patterns 7, 535543 (2007).
69. Fallon, P.G. etal. IL-4 induces characteristic Th2
responses even in the combined absence of IL-5, IL-9,
and IL-13. Immunity 17, 717 (2002).
70. Finkelman, F.D. etal. Interleukin-4- and interleukin-13-
mediated host protection against intestinal nematode
parasites. Immunol. Rev. 201, 139155 (2004).
71. Barner, M., Mohrs, M., Brombacher, F. & Kopf, M.
Differences between IL-4R -deficient and
IL-4-deficient mice reveal a role for IL-13 in the
regulation of Th2 responses. Curr. Biol. 8, 669672
(1998).
72. McKenzie, G.J., Bancroft, A., Grencis, R.K. &
McKenzie, A.N. A distinct role for interleukin-13 in
Th2-cell-mediated immune responses. Curr. Biol. 8,
339342 (1998).
73. Voehringer, D., Reese, T.A., Huang, X., Shinkai, K. &
Locksley, R.M. Type 2 immunity is controlled by IL-4/
IL-13 expression in hematopoietic non-eosinophil cells
of the innate immune system. J.Exp. Med. 203,
14351446 (2006).
74. Kang, Z. etal. Epithelial cell-specific Act1 adaptor
mediates interleukin-25-dependent helminth
expulsion through expansion of Lin
c-Kit
+
innate cell
population. Immunity 36, 821833 (2012).
75. Zheng, Y. etal. Interleukin-22 mediates early host
defense against attaching and effacing bacterial
pathogens. Nature Med. 14, 282289 (2008).
76. Zenewicz, L.A. & Flavell, R.A. Recent advances in
IL-22 biology. Int. Immunol. 23, 159163 (2011).
77. Vallance, B.A., Deng, W., Knodler, L.A. & Finlay, B.B.
Mice lacking T and B lymphocytes develop transient
colitis and crypt hyperplasia yet suffer impaired
bacterial clearance during Citrobacter rodentium
infection. Infect. Immun. 70, 20702081 (2002).
REVI EWS
REVI EWS
78. De Luca, A. etal. IL-22 defines a novel immune
pathway of antifungal resistance. Mucosal Immunol.
3, 361373 (2010).
79. Sonnenberg, G.F. etal. Innate lymphoid cells promote
anatomical containment of lymphoid-resident
commensal bacteria. Science 336, 13211325
(2012).
80. Wolterink, R.G. etal. Pulmonary innate lymphoid
cells are major producers of IL-5 and IL-13 in murine
models of allergic asthma. Eur. J.Immunol. 42,
11061116 (2012).
81. Halim, T.Y., Krauss, R.H., Sun, A.C. & Takei, F.
Lung natural helper cells are a critical source of Th2
cell-type cytokines in protease allergen-induced
airway inflammation. Immunity 36, 451463 (2012).
82. Ikutani, M. etal. Identification of innate
IL-5-producing cells and their role in lung eosinophil
regulation and antitumor immunity. J.Immunol. 188,
703713 (2012).
83. Jackson, D.J., Sykes, A., Mallia, P. & Johnston, S.L.
Asthma exacerbations: origin, effect, and
prevention. J.Allergy Clin. Immunol. 128,
11651174 (2011).
84. Maloy, K.J. & Powrie, F. Intestinal homeostasis and
its breakdown in inflammatory bowel disease.
Nature 474, 298306 (2011).
85. Fuss, I.J. etal. Nonclassical CD1d-restricted
NK T cells that produce IL-13 characterize an atypical
Th2 response in ulcerative colitis. J.Clin. Invest. 113,
14901497 (2004).
86. Heller, F., Fuss, I.J., Nieuwenhuis, E.E., Blumberg, R.S.
& Strober, W. Oxazolone colitis, a Th2 colitis model
resembling ulcerative colitis, is mediated by IL-13-
producing NK-T cells. Immunity 17, 629638
(2002).
87. Powell, N. etal. The transcription factor T-bet
regulates intestinal inflammation mediated by
interleukin-7 receptor
+
innate lymphoid cells.
Immunity 37, 674684 (2012).
88. Lochner, M. etal. Microbiota-induced tertiary
lymphoid tissues aggravate inflammatory disease in
the absence of RORt and LTi cells. J.Exp. Med. 208,
125134 (2011).
89. Geremia, A. etal. IL-23-responsive innate lymphoid
cells are increased in inflammatory bowel disease.
J.Exp. Med. 208, 11271133 (2011).
90. Takayama, T. etal. Imbalance of NKp44
+
NKp46

and NKp44
NKp46
+
natural killer cells in the
intestinal mucosa of patients with Crohns disease.
Gastroenterology 139, 882892 (2010).
91. Fuss, I.J. etal. Disparate CD4
+
lamina propria (LP)
lymphokine secretion profiles in inflammatory bowel
disease. Crohns disease LP cells manifest increased
secretion of IFN-, whereas ulcerative colitis LP cells
manifest increased secretion of IL-5. J.Immunol. 157,
12611270 (1996).
92. Sawa, S. etal. RORt
+
innate lymphoid cells regulate
intestinal homeostasis by integrating negative signals
from the symbiotic microbiota. Nature Immunol. 12,
320326 (2011).
93. Besnard, A.G. etal. Dual role of IL-22 in allergic
airway inflammation and its cross-talk with IL-17A.
Am. J.Respir. Crit. Care Med. 183, 11531163
(2011).
94. Schnyder, B., Lima, C. & Schnyder-Candrian, S.
Interleukin-22 is a negative regulator of the
allergic response. Cytokine 50, 220227
(2010).
95. Taube, C. etal. IL-22 is produced by innate lymphoid
cells and limits inflammation in allergic airway disease.
PLoS ONE 6, e21799 (2011).
96. Takahashi, K. etal. IL-22 attenuates IL-25
production by lung epithelial cells and inhibits
antigen-induced eosinophilic airway inflammation.
J.Allergy Clin. Immunol. 128, 10671076 (2011).
97. Barlow, J.L., Flynn, R.J., Ballantyne, S.J. &
McKenzie, A.N. Reciprocal expression of IL-25
and IL-17A is important for allergic airways
hyperreactivity. Clin. Exp. Allergy 41, 14471455
(2011).
98. Wilhelm, C. etal. An IL-9 fate reporter demonstrates
the induction of an innate IL-9 response in lung
inflammation. Nature Immunol. 12, 10711077
(2011).
99. Huntington, N.D., Vosshenrich, C.A. & Di Santo, J.P.
Developmental pathways that generate natural-killer-
cell diversity in mice and humans. Nature Rev.
Immunol. 7, 703714 (2007).
100. Jackson, J.T. etal. Id2 expression delineates
differential checkpoints in the genetic program of
CD8
+
and CD103
+
dendritic cell lineages. EMBO J.
30, 26902704 (2011).
101. Gascoyne, D.M. etal. The basic leucine zipper
transcription factor E4BP4 is essential for natural killer
cell development. Nature Immunol. 10, 11181124
(2009).
102. Kamizono, S. etal. Nfil3/E4bp4 is required for the
development and maturation of NK cells in vivo.
J.Exp. Med. 206, 29772986 (2009).
103. Yang, X.O. etal. T helper 17 lineage differentiation is
programmed by orphan nuclear receptors ROR and
ROR. Immunity 28, 2939 (2008).
104. Samson, S.I. etal. GATA-3 promotes maturation,
IFN- production, and liver-specific homing of NK cells.
Immunity 19, 701711 (2003).
105. Veldhoen, M. etal. The aryl hydrocarbon receptor links
T
H
17-cell-mediated autoimmunity to environmental
toxins. Nature 453, 106109 (2008).
106. Aliahmad, P., de la Torre, B. & Kaye, J. Shared
dependence on the DNA-binding factor TOX for the
development of lymphoid tissue-inducer cell and NK
cell lineages. Nature Immunol. 11, 945952 (2010).
107. Ohno, S. etal. Runx proteins are involved in
regulation of CD122, Ly49 family and IFN-
expression during NK cell differentiation. Int.
Immunol. 20, 7179 (2008).
108. Tachibana, M. etal. Runx1/Cbf2 complexes are
required for lymphoid tissue inducer cell
differentiation at two developmental stages.
J.Immunol. 186, 14501457 (2011).
109. Scium,G. etal. Distinct requirements for T-bet in gut
innate lymphoid cells. J. Exp. Med. 3 Dec 2012
(doi:10.1084/jem.20122097).
Acknowledgements
The authors would like to thank S. Bell, C. Oliphant and S.
Scanlon for critical appraisal of the manuscript. J.A.W. and
A.N.J.M. are supported by the American Asthma Foundation.
Competing interests statement
The authors declare no competing financial interests.
FURTHER INFORMATION
Andrew N.J.McKenzies homepage: http://www2.mrc-lmb.
cam.ac.uk/group-leaders/h-to-m/a-mckenzie
ALL LINKS ARE ACTIVE IN THE ONLINE PDF
REVI EWS

Nri 3349

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Nri 3349

Uploaded by

Copyright:

Available Formats

The orchestration of immune responses by T cells

through their release of a complex repertoire of

) ILC subsets do not

ILCs, natural killer (NK) cells and

cells scattered among fetal

CLPs and require Notch signals and ID2 expression for

cells were the major source of

) is consistent with that of anILC3.

cells expressed IL-17A and

cells to colonize lymph

You might also like