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Taming the Beast within: Regulation of and Function

This information is current as Wei Xu and James P. Di Santo of September 28, 2021. J Immunol 2013; 191:4489-4496; ; doi: 10.4049/jimmunol.1301759 http://www.jimmunol.org/content/191/9/4489 Downloaded from

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology

Taming the Beast within: Regulation of Innate Lymphoid Cell Homeostasis and Function Wei Xu and James P. Di Santo Although substantial parallels have been made between Phenotypic and functional parallels between ILC and Th cell subsets regulation of production ILC1s. NK cells were discovered some 30 years ago owing to by innate lymphoid cell (ILC) and Th cell subsets, we their ability to spontaneously eliminate tumor cell targets are still learning how ILC subsets are regulated during (“natural ”) (3). NK cells also eliminate cells infec- immune responses. Critical factors that promote ILC ted by , intracellular pathogens, or that are “stressed” development and stimulate their effector functions have by or inflammation through / or the been identified, but mechanisms that control their ho- FasL/Fas pathway or by releasing such as IFN-g that meostasis and downregulate their cytokine secretion re- prime pathogen-infected (4). Remarkably, these Downloaded from main poorly understood. In this review, we consider same effector mechanisms are also used by CD8+ CTLs (and by some of the potential positive and negative regulators a subset of CD4+ Th1 cells) of the adaptive , of ILC homeostasis and function in physiological and thus identifying NK cells and CTLs as the “professional killers” pathological conditions. The Journal of Immunology, of the innate and adaptive immune systems, respectively. 2013, 191: 4489–4496. Functional differentiation of NK cells and CD8 CTLs is regulated by the transcription factors T-bet (Tbx21)and http://www.jimmunol.org/ Eomes (5, 6), resulting in the capacity to produce potent he recent discovery of a novel family of innate lym- proinflammatory cytokines, including IFN-g, TNF-a, and a phoid cells (ILCs) has drawn new attention to the early variety of myeloid cell–attracting . IFN-g secretion T events in innate immune responses and their effects by CD4+ Th1 cells, CD8+ CTLs, and NK cells is potently on the generation of adaptive immunity. ILCs are important activated by cytokines (e.g., IL-12, IL-18), suggesting a parallel sources of cytokines, which promote immune responses to mode of functional regulation (7). Based on their similarities infections, orchestrate lymphoid organogenesis, and facilitate to CD4+ Th1 and CD8+ T cells that predominantly produce

epithelial tissue remodeling. Based on their phenotype and IFN-g, NK cells have been included within the ILC1 subset (1). by guest on September 28, 2021 functional characteristics, ILCs are classified into three groups Recently, novel subsets of ILC1s were identified in human (1, 2). Group 1 ILCs (ILC1s) include conventional NK cells mucosal sites (8, 9). A human ILC1 subset that lacks expres- and a newly identified innate cell population that lacks most sion of conventional NK cell surface markers (such as CD56, of the receptors found on NK cells (see below); both are as well as the NCRs NKp44 and NKp46) and cytolytic ef- potent producers of IFN-g. Group 2 ILCs () secrete IL- fector molecules has been identified that strongly produced 5 and IL-13 following stimulation by IL-25 or IL-33 (“alar- IFN-g in response to IL-12 and IL-18 and showed high-level min”) released by damaged epithelial cells or activated mye- expression of Tbx21, Cxcr3, and Ccl3, demonstrating a close loid cells. Group 3 ILCs (ILC3s) include lymphoid tissue resemble to CD4+ Th1 cells. These IFN-g–producing ILC1s + inducer (LTi) cells, natural cytotoxicity receptor (NCR) and were found to be present in the intestine of patients with 2 + NCR retinoic acid–related orphan receptor (ROR)gt sub- Crohn’s disease, an illness characterized by increased levels sets that produce cytokines IL-17A and/or IL-22. Function- of Th1 cytokines. Another report identified a subset of NK ally, the ILC family can be considered as “innate” equivalents receptor–expressing ILC1s in mucosal (9). These of T effector cells (cytotoxic CD8 T cells and differentiated NKp44+CD103+ ILCs also express transcription factor T- CD4 Th subsets), as they secret a similar array of cytokines bet and Eomes and can secrete large amounts of IFN-g, and activate an analogous set of target cells. Regulation of ILC CCL4, and TNF-a in response to IL-12 and IL-15. Owing effector functions can be considered as resulting from a “bal- to their selective expression of integrins and CD103, these ance” of activating and inhibitory signals (Fig. 1). ILC1s were proposed to be the innate counterparts of tissue-

Innate Immunity Unit, Institut Pasteur, 75724 Paris, France; and INSERM Unite´ 668, Paris, France. E-mail addresses: [email protected] (W.X.) and james.di-santo@pasteur. 75724 Paris, France fr (J.P.D.) Received for publication July 9, 2013. Accepted for publication August 19, 2013. Abbreviations used in this article: ILC, innate lymphoid cell; ILC1, group 1 ILC; ILC2, group 2 ILC; ILC3, group 3 ILC; LTi, lymphoid tissue inducer; NCR, natural cyto- This work was supported by grants from the Fondation pour la Recherche Me´dicale and toxicity receptor; ROR, retinoic acid–related orphan receptor; Treg, regulatory ; the Institut National du Cancer (to W.X.). This work was also supported by grants from TSLP, thymic stromal lymphopoietin. the Institut Pasteur, INSERM, the Ligue Nationale Contre le Cancer (Equipe Labellise´e Ligue Contre le Cancer), and by the Agence National pour la Recherche (Program Blanc Ó “Gut ILC”). Copyright 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 Address correspondence and reprint requests to Dr. Wei Xu and Prof. James P. Di Santo, Innate Immunity Unit, Institut Pasteur, 25 Rue du Docteur Roux, 75724

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1301759 4490 BRIEF REVIEWS: REGULATING ILC HOMEOSTASIS AND FUNCTION

FIGURE 1. Factors that regulate ILC homeostasis and function. ILC subsets express multiple receptors for sol- uble factors that can induce cell differentiation, promote homeostatic expansion, and activate effector functions. These include cytokines of the common cytokine receptor g-chain family, the IL-1 family, the IL-17 family, and/or the IL-12/IL-23 family. Some of the cytokine require- ments are broadly used by all ILC subsets (e.g., IL-7), whereas others are unique to a particular subset (e.g., IL- 33 for ILC2). Modulation of ILC expansion and func- tions may be achieved through signals emanating from inhibitory receptors (Ly49, KIR, KLRG1) or receptors for immunosuppressive cytokines, including IL-10 and TGF-b. A balance between the positive and negative sig- Downloaded from nals is essential to regulate ILC function to restrict path- ogenic microbes while delimiting activity that can lead to autoimmunity. http://www.jimmunol.org/

resident memory CD8+ T cells. Whether these ILC1 subsets mine the protective versus pathological properties of ILC2s exist in other species or at other nonmucosal sites is not remain to be determined but could provide a means to boost known. immune responses and avoid collateral tissue damage. ILC2s. Recently, several groups have described innate cells that ILC3s. LTi cells represent the founding member of the ILC3s.

rapidly produced “Th2-like” cytokines, including IL-5 and LTi cells initiate organogenesis of lymph nodes and Peyer’s by guest on September 28, 2021 IL-13 (10–12). These cell subsets were initially referred to patches during fetal life by interacting with the local mesen- as “natural helper cells,” “,” or “innate helper 2 cells” chymal cells (21, 22). Small numbers of LTi-like cells can be but have recently been renamed ILC2s (1). ILC2s are found found after birth that are required for induced tertiary systemically where they initiate Th2 responses during helminth lymphoid tissues (23). Fetal and adult LTi cells have the and viral infections or in the context of inflammatory diseases, capacity to produce IL-22 and/or IL-17A (24, 25) and thus such as allergic . ILC2s express receptors for IL-25 resemble innate versions of RORgt-dependent Th17 cells. (IL-17RB), for IL-33 (T1/ST2), and for thymic stromal Recently, several groups have identified RORgt+ innate cells lymphopoietin (TSLP). Stimulation of ILC2s with IL-25, that express NCRs, produce IL-22, and are highly enriched IL-33, or TSLP triggers production of IL-5 and IL-13 (the in the intestinal mucosa (25–29). Similar to LTi cells, these feature cytokines of type 2 immunity) as well as IL-6, IL-10, NCR+ ILC3s require the transcription factor Rorc for their and GM-CSF (1, 2). Because ILC2s coexpress receptors for development. Additionally, the aryl hydrocarbon receptor was IL-25, IL-33, and TSLP, ILC2s may exert their function shown to be necessary for the optimal expression of IL-22 through different signaling pathways depending on micro- by distinct ILC3 subsets (30–32). IL-17A and IL-22 have environment and the relative levels of these cytokines in tissues. major effects on epithelial cells of many tissues and are crucial Development and type 2 cytokine secretion by ILC2s are in defense against extracellular pathogens such as Salmonella, regulated by Gata3 (13–15). Notch1, Tcf7, and Rora are es- Citrobacter,andKlebsiella (26, 33–35). It has also been sential transcriptional regulators of ILC2 development via suggested that expression of IL-17A promotes the inflam- Gata3-dependent and -independent mechanisms (16, 17). matory phenotype in some autoimmune diseases (36). ILC2s provide essential innate sources of IL-5 and IL-13 during Although IL-22 is generally considered as tissue-protective helminth infections (such as Nippostrongylus brasiliensis) and are or reparative, overexpression of IL-22 in some cases maybe sufficient to mediate eosinophilia and worm clearance upon associated with disease progression, including tumor trans- activation by exogenous cytokines IL-25 and IL-33 (12, 18). In formation (37–39). the context of pulmonary viral infections, ILC2s produce Several cell surface markers (CD4, c-Kit, CCR6, MHC class (19) that promotes tissue repair. In contrast to II) and transcription factors (T-bet) identify subsets of these protective functions of ILC2s, overproduction of IL-5 and RORgt+ ILC3s with different tissue localizations and func- 2 IL-13 by ILC2s may play a role in increased airway hyperre- tional attributes (40–44). For example, CD4+CD3 IL-7Ra+ activity that characterizes allergic asthma (20). Thus, ILC2s LTi cells lack NCR and T-bet expression but are CCR6+, have both beneficial and disease-provoking characteristics (a collect in intestinal isolated lymphoid follicles, and coexpress recurrent theme in ILC biology). The mechanisms that deter- IL-17A and IL-22 (40). Other ILC3 subsets include T-bet+ The Journal of Immunology 4491

2 2 2 CCR6 and T-bet CCR6 cells with different levels of NCR have been described that are essential for homeo- expression (41). In these subsets, IL-22 and IL-17A production stasis and keep the in check. is associated with NCR expression and negatively correlated The transcription factor Foxp3 is a master regulator of with T-bet expression. The expression of T-bet in RORgt+ CD4+ Treg fate and its expression correlates with the ability ILC3s is somewhat surprising, as T-bet is a key regulator of of Tregs to suppress T cell activation. Do ILC equivalents of IFN-g expression in Th1 cells as well as ILC1 subsets. Indeed, Tregs exist? There have been no reports of a Foxp3-expressing 2 2 T-bet–expressing CCR6 RORgt+ ILCs can produce IFN-g ILC population, but regulatory Foxp3 ILCs may use alter- (41), reminiscent of IL-17/IFN-g double producer Th17 cells native (Foxp3-independent) pathways to generate immune (45). suppression. Tregs modulate immune responses through re- lease of inhibitory cytokines, including IL-10, TGF-b,and Do ILCs demonstrate plasticity in their effector functions? IL-35 (51, 52). Both IL-10 deficiency and TFG-b deficiency can lead to inflammatory disease in various organ systems (53, Many studies have demonstrated that phenotypic and func- 54). ILCs expressing IL-10, TGF-b, and perhaps IL-35 could tional properties of Th cells are not “fixed” and can “evolve,” represent potential regulatory ILCs. giving rise to a T cells with cytokine profiles characteristic of Disruption of Foxp3 in mice results in impaired generation a different Th subset under certain circumstances (46). Th cell and function of Tregs, thus leading to deadly lymphoproli- plasticity relies on the environmental signals and the conse- ferative disorders that are characterized by hyperactivation of quent activation and/or suppression of specific transcription adaptive immunity. To what extent Treg deficiency also results Downloaded from factors. Functional plasticity has been observed in both hu- in ILC dysregulation is not known. Generalized inflammation man and mouse ILC3s (47, 48). IL-22–producing ILC3s can may indirectly promote ILC recruitment and activation. Al- coexpress IFN-g in response to cytokine stimulation (in- ternatively, Tregs may directly suppress ILCs. Recent reports cluding IL-12 and IL-18 in the presence of IL-2 and IL-7). have demonstrated that Tregs regulate NK cell subset devel- These IFN-g–producing ILC3s retain RORgt transcripts, opment through modulation of soluble factors (IL-2) that can although at a lower level than are seen in IL-22–producing stimulate early NK cell progenitors (55, 56). Treg production http://www.jimmunol.org/ cells, and they express higher levels of T-bet. Interestingly, of TGF-b and IL-10 (and other factors) may directly influ- a study using a genetic lineage tracing (“fate mapping”) + ence ILC subset activation, thereby providing a direct control revealed that some NCR ILC3s can lose RORgt expression, of ILC homeostasis and effector function (see below). possibly due to the deprivation of stabilizing signals from the environment (49). The reduction of RORgt expression gen- Factors regulating ILC homeostasis and function erates a change in the cytokine production profile with an Thecytokinemilieucomprisesthosesolubleandcell- increase in IFN-g and a decrease in IL-22. Note that these ex- 2 associated factors that are available within tissues or in the RORg–expressing cells (NCR+RORgt ) are difficult to dis-

circulation, and it represents one of the most important ex- by guest on September 28, 2021 tinguish from conventional NK cells in the absence of a line- trinsic factors that condition lymphocyte biology within di- age-tracing model. verse microenvironments. The availability, composition, and ILC functional plasticity may be instructed by the micro- levels of factors within the cytokine milieu have profound environment to protect local tissues from pathologies. In a 2 2 2 2 effects on ILC differentiation. ILCs are derived from common chronic colitis model (Tbx21 / Rag / ulcerative colitis mice), lymphoid progenitors in the where stromal cells colonic ILC3s have a selective increase in IL-17A production 2 2 produce essential cytokines for their development and sur- that drives pathology (48). In contrast, Rag / mice exhibit vival, an important one being IL-7. In the peripheral lym- ILC3s that produce both IL-17A and IFN-g. Because Tbx21 phoid organs or mucosal sites, ILCs may undergo further controls IFN-g production in both Th17 cells and ILC3s, the maturation and activation due to cytokines that promote ILC inability of ILC3s to achieve a functional plasticity may ex- effector functions (IL-12, IL-23, IL-25, IL-33), whereas later plain the excessive IL-17A production. The plasticity of IFN-g phases of the response may be dominated by “suppressive” production in non–Th1 cells can be explained by the bi- cytokines (TGF-b, IL-10) that downregulate ILC function valent H3K4 and H3K27 modification of the Tbx21 gene (Fig. 2). Moreover, mucosal sites (, lung, intestine, and in other Th cell subsets (50). Whether similar epigenetic colon) harbor unique commensal microbial communities that modifications of lineage-specific transcription factors or cy- likely interact with the epithelial barriers and trigger site- tokine genes also exist in the ILC subsets needs to be assessed specific cytokines and profiles. As such, these dif- by further studies. ferent niches may influence the composition, magnitude, and quality of the ILC immune responses. Is there a dedicated regulatory ILC subset? Common cytokine receptor g-chain family of cytokines. Develop- Uncontrolled immune responses with excessive production ment of all ILC subsets is facilitated by cytokines (IL-2, IL-4, of proinflammatory cytokines can be deleterious to the hosts. IL-7, IL-9, IL-15, and IL-21) that share the common cytokine Maintenance of immune homeostasis may be imposed by receptor g-chain in their receptor complexes. These cytokines limiting resources (regulation of the availability of cytokines or regulate the development and homeostasis of innate and adap- other activating signals, thereby promoting competition) or tive as well as their functions during immune through dominant suppressive mechanisms (production of responses. Mice lacking the common g-chain are severely soluble or cell-associated inhibitory soluble factors that can deficient in all known ILC subsets, and it has been shown transduce negative signals). In adaptive immunity, dedicated that IL-7 is necessary for generation of group 2 and 3 ILCs, subsets of regulatory T cells (Tregs), including “natural” or whereas IL-15 dominantly promotes NK cell development induced CD4+ Tregs, Tr1 cells, and subsets of CD8+ T cells, (1). Because roles for IL-2, IL-7, and IL-15 in T, B, and 4492 BRIEF REVIEWS: REGULATING ILC HOMEOSTASIS AND FUNCTION

FIGURE 2. The cytokine milieu reg- ulates ILC homeostasis and activation. Under steady-state conditions, common g-chain receptor family cytokines pro- duced by epithelial cells or other immune cells promote ILC development and main- tain ILC homeostasis via survival and pro- liferation signals. Following pathogenic infection or inflammation, alarmins re- leased by epithelial cells (e.g., IL-25, IL- 33) or proinflammatory cytokines pro- duced by dendritic cells and macrophages (e.g., IL-12, IL-18, IL-23) activate ILCs and trigger their effector functions. At later stages of the response, ILCs may receive suppressive signals (e.g., IL-10, TGF-b) Downloaded from from regulatory T cells, dendritic cells, macrophages, or from putative regulatory ILCs that downregulate ILC functions. http://www.jimmunol.org/

NK cell biology has been extensively reviewed (57), we will TSLP signals via the TSLP receptor complexed with the IL- focus on the role for these cytokines in regulating ILC2 and 7Ra-chain. Overexpression of TSLP restored T and ILC3 homeostasis and function. differentiation as well as development in IL- 2/2 IL-2. Murine ILC2s express IL-2Ra (CD25) and IL-2 can 7 mice (63). Whether TSLP can compensate for IL-7 in promote the expansion of ILC2s in in vitro combination promoting generation of ILC2 and other ILC3 subsets from

with IL-25 or IL-33 (11). It was suggested that the main- early lymphoid progenitors is not known. TSLP is constitu- by guest on September 28, 2021 tenance of ILC2 numbers and cytokine production requires tively expressed in intestinal epithelial cells (64). Deficiency in 2 2 the presence of T cells, as N. brasiliensis infection in Rag / TSLP signaling results in a reduction of LTi-like cells but not mice failed to sustain the ILC2 population or the levels of IL-22–producing ILC3 in the intestine, whereas the numbers 2 2 IL-5 and IL13 production (10). Delivery of exogenous IL-2 of both ILC3 subsets are decreased in IL-7 / mice, which 2 2 into Rag2 / mice was sufficient to overcome this defect, suggests that these two cytokines have both redundant and suggesting that IL-2 provided by T cells or NKT cells may distinct roles in ILC3 biology (49). be critical for ILC2 homeostasis (58). Whereas subsets of Interestingly, transgenic overexpression of TSLP was asso- splenic ILC3s express CD25, these cells were unaffected in ciated with allergic inflammatory diseases such as atopic der- mice deficient in IL-2 signaling, ruling out a critical role for matitisandasthmas(65),whereasdisruptionofTSLPsignaling IL-2 in ILC3 development (59). It remains possible that IL-2 led to defective expression of pathogen-specific Th2 cytokine might modify the functional capacity of certain ILC3 subsets. responses and a failure to control infection by Trichuris (64). IL-7 family: IL-7 and TSLP. IL-7 signals through IL-7R One explanation for this is that TSLP can trigger rapid IL-13 composed of IL-7Ra (CD127) and the common g-chain. secretion and promote significant ILC2 expansion. TSLP- IL-7Ra is also used by TSLP, a paralog of IL-7 that signals mediated production of IL-13 is STAT5- and GATA3- in a common g-chain–independent fashion. Early stages of dependent and can be further enhanced by costimulation require IL-7 for the maintenance of IL-7Ra+ with IL-33 (66). It was recently shown that skin-associated multipotent progenitor cells, including common lymphoid ILC2s are dependent on TSLP but not IL-33 or IL-25 sig- progenitors that give rise to all ILC subsets in addition to T naling for their secretion of Th2 cytokines (67). It is possible and B cells. ILC2 and ILC3 are IL-7Ra+ and these ILC that TSLP signaling can promote Th2 responses in distinct subsets are strongly reduced in the absence of IL-7 (2). ILC2 subsets in a tissue-specific fashion. During both fetal and adult life, IL-7 signaling regulates IL-1 family: IL-1b, IL-18, and IL-33. The IL-1 family of the size of the LTi cell pool by promoting cell survival (60–62). cytokinesincludes11members(IL-1a,IL-1b,IL-1Ra, In a similar fashion, IL-7 may sustain the homeostasis of ILC2 IL-18, IL-33, IL-36Ra,IL-36a,IL-37,IL-36b,IL-36g, and NCR+ ILC3. In adults, IL-7 is proposed to stabilize and IL-38) that have potent effects on hematopoietic and RORgt expression in ILC3, although the underlying mech- nonhematopoietic cells (reviewed in Ref. 68). IL-1 family anism remains obscure (49). Further studies using conditional cytokines signal through specific receptors containing a IL-7R ablation or tissue-specific deletion of IL-7 may provide Toll/IL-1R homology domain that leads to the activation better insights into the role for IL-7 signaling in mature ILC of transcription factors such as NF-kBandAP-1through homeostasis and function. a MyD88/TRAF6 pathway. Some IL-1 family cytokines The Journal of Immunology 4493

(IL-1b, IL-18) are produced as preproteins requiring cleavage absence of IL-25, basal IL-22 levels are increased. This effect by inflammasome-induced caspase-1 to become biologically is contact-dependent, although the cell–cell interactions are active. IL-33, in contrast, is translated as a fully biologically yet to be defined. active protein and can be processed into a more active form IL-12 and IL-23. IL-12 and IL-23 are proinflammatory by specific enzymes in neutrophils, but it is degraded and cytokines that share structural and functional activities. IL-12 inactivated by caspases and other extracellular proteases (69). is a heterodimeric cytokine comprised of the p35 and p40 IL-1 was initially described as a cofactor for T cell activation subunits, whereas IL-23 has a unique p19 subunit but uses that synergized with other signals to activate cytokine secretion the same p40 subunit. Both IL-12 and IL-23 are released (70). A similar biology may exist for the effects of some IL-1 by APCs, mainly the CD11chi dendritic cells and macro- family cytokines that stimulate ILCs. Concerning this family of phages in response to microbial stimuli or stress (76). IL-23 soluble factors, the cytokines IL-1b, IL-18, and IL-33 have is constitutively expressed in part of the intestine (77) and been shown to have effects on distinct ILC subsets. stimulates secretion of Th17 cytokines (IL-17A, IL-17F, IL-1b is a member of the IL-1 cytokines that also include IL-22) from T cells and non–T cells, including ILC3. In IL-1a and the soluble IL-1Ra that antagonizes IL-1 respon- contrast, IL-12 directs differentiation of Th1 T cells and ses. IL-1a and IL-1b have similar effects on multiple cell promotes IFN-g production from T cells, NK cells, and types and promote sterile inflammation via activation of mac- ILC1s through T-bet (5, 6, 8, 41, 47). IL-23 induces secretion rophages, neutrophils, NK cells, T cells, and stromal fibroblasts of IL-17/IL-22/IFN-g in both LTi/LTi-like cells and NCR+ through chemokines, proinflammatory cytokines, and enzymes ILC3s that are associated with IL-23–driven innate intestinal Downloaded from involved in the production of prostaglandins or NO. Impor- inflammation (24–27, 29, 42, 78). In Th17 cells, IL-23 tantly, IL-1b plays an inductive role in Th17 responses and can functions to promote cell proliferation and maintain their potently stimulate differentiated Th17 cells (70). The IL-1R is phenotype (36). Whether IL-23 is responsible for ILC3 g + expressed by ROR t ILC3s in mice and humans and can act expansion/maintenance of ILC3s remains to be determined. in concert with IL-23 to stimulate RORgt+ ILC3s for pro- TGF-b. More than 40 members of the TGFs have been duction of IL-17A and IL-22 (47). http://www.jimmunol.org/ identified and the TGF-b subfamily has 6 members, of which IL-18 was first discovered as an IFN-g–inducing factor that TGF-b1 is best characterized for its potent effects on the promoted cytokine secretion from T cells (71). IL-18 acts immune system. TGFs are produced as latent proteins that alone in this respect, but it can also potently synergize with require maturation to achieve full activity. Active TGF-b IL-12 to boost IFN-g production from Th1 cells, NK cells, and human ILC1s (8). Moreover, IL-18 appears to be re- binds broadly expressed heterodimeric receptors that signal quired for functional “priming” of NK cells (72). Whether through SMAD adaptors to regulate gene expression (79). b IL-18 has a regulatory role in other ILC subsets is not known. TGF- 1–deficient mice manifest a multiorgan infiltrative disease that occurs early in life and results is death within 3–4

IL-33 is a proinflammatory molecule that is released by by guest on September 28, 2021 necrotic cells after tissue injury (73). Administration of IL-33 wk (80). The precise mechanisms responsible for the demise in mice triggers eosinophil-associated inflammation in the lung of TGF-b1–deficient mice are only partly understood. One andgutthatrequiresIL-13productionbutisindependent clear effect is the absence of Tregs, as TGF-b1 can potently of adaptive lymphocytes, mast cells, , or NK cells prime the differentiation of this subset from (74). It was later shown that ILC2s are responsible for this precursors. As such, the widespread T cell activation that IL-33–mediated eosinophilia via ILC2 expansion/accumulation accompanies TGF-b1 deficiency in some ways resembles that and cytokine secretion. It has also been demonstrated that of Treg deficiency following ablation of Foxp3. More- IL-33 synergizes with IL-7 for Notch-induced development over, much of the disease phenotype in TGF-b1 knockout of ILC2s from common lymphoid progenitors in vitro mice can be recapitulated by overexpression of a dominant- (17). negative TGF-bRII transgene in the T cell lineage (81). Thus, IL-25. IL-25 (IL-17E) belongs to the IL-17 cytokine family TGF-b production by Tregs (Tr1) has important consequences with six members in total, IL-17A–F. IL-25 was shown to for immune homeostasis of adaptive lymphocytes. play an important role in the development of Th2-mediated The role for TGF-b in regulating innate lymphocytes has allergic inflammation by regulating CD4+ Tcellsand not been fully explored. Overexpression of dominant-negative ILCs (75). IL-25 can trigger ILC2s for rapid clearance of TGF-bRII under the CD11c promoter unexpectedly resulted N. brasiliensis acute infection but also is implicated in the in the expansion of an activated NK cell population that induction of acute lung inflammation during (75). It strongly produced IFN-g. This was shown to be due to low- has been shown that both IL-25 and IL-33 treatments in level expression of CD11c in the NK lineage, generating 2 2 Rag / mice are sufficient to bypass the requirement for a blockade of TGF-b signaling in mature NK cells. This re- adaptive immunity during worm expulsion (12). However, sult demonstrated that TGF-b plays a suppressive role in NK IL-25 and IL-33 may stimulate ILC2s to different states of cell homeostasis (82). Whether other ILCs are under negative activation as defined by the expression of certain surface regulation by TGF-b remains to be shown, but if this is the markers (CD25, Sca1) (75). IL-25–stimulated ILC2s produce case, one can also expect that some aspects of the disease other cytokines such as IL-9 that contribute to the development phenotype in TGF-b–deficient mice may also be secondary to of immunity and inflammation in the airway. hyperactivation of various ILC subsets. Interestingly, IL-25 appears capable of regulating IL-22 IL-10. IL-10 is a broadly immunosuppressive cytokine, in- responses from ILC3s. One model proposes that commensal hibiting production and release of inflammatory cytokines microbiota stimulate IL-25 expression that can act via dendritic by macrophages and monocytes, especially at mucosal sites. cells that subsequently reduce ILC3-derived IL-22 (29). In the IL-10 is produced by most cells of the immune system 4494 BRIEF REVIEWS: REGULATING ILC HOMEOSTASIS AND FUNCTION

(dendritic cells, macrophages, T and B cells) and triggers effects thologies. A better understanding of the factors that positively through a receptor comprised of IL-10Ra- and IL-10Rb- and negatively regulate ILC homeostasis and function could chains (83). IL-10 plays an important regulatory role in Th have an impact on vaccine development and the treatment of cell differentiation, acting to inhibit IL-12 production and autoimmune diseases. thereby reduce Th1 development and IFN-g production. Additionally, IL-10 may induce “tolerogenic” dendritic cells Acknowledgments that produce IL-1R antagonist, TGF-b, and, in humans, We thank all of members of Innate Immunity Unit for valuable discussions. immunosuppressive HLA-G (84). Loss of IL-10 signaling leads to systemic inflammation and an intestinal wasting syn- Disclosures drome that appears triggered by commensal (53). The authors have no financial conflicts of interest. 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