Interleukin-22-Producing Natural Killer Cells and Lymphoid Tissue Inducer-like Cells in Mucosal Immunity
2009; Cell Press; Volume: 31; Issue: 1 Linguagem: Inglês
10.1016/j.immuni.2009.06.008
ISSN1097-4180
Autores Tópico(s)Reproductive System and Pregnancy
ResumoBlood, lymphoid tissues, and placenta contain diverse subpopulations of natural killer (NK) cells that possess distinct immune functions. Recent studies have shown that human and mouse gut-associated lymphoid tissues harbor a unique NK cell subset that specializes in production of interleukin (IL)-22. This cytokine plays a role in host defense of mucosal barriers, although dysregulated secretion may cause autoimmune disease. In parallel, human fetal lymphoid tissue inducer (LTi) cells and mouse adult LTi-like cells in secondary lymphoid tissues were found to release IL-22, as well as IL-17, a proinflammatory cytokine that mediates host defense against extracellular pathogens. Here, we compare these recently identified immune cells, reviewing what is known about their anatomical location, differentiation requirements, function, and potential involvement in host defense and autoimmunity. Finally, we discuss the challenges faced in furthering our understanding of the developmental relationships and role of NK and LTi-like cells in mucosal immune responses. Blood, lymphoid tissues, and placenta contain diverse subpopulations of natural killer (NK) cells that possess distinct immune functions. Recent studies have shown that human and mouse gut-associated lymphoid tissues harbor a unique NK cell subset that specializes in production of interleukin (IL)-22. This cytokine plays a role in host defense of mucosal barriers, although dysregulated secretion may cause autoimmune disease. In parallel, human fetal lymphoid tissue inducer (LTi) cells and mouse adult LTi-like cells in secondary lymphoid tissues were found to release IL-22, as well as IL-17, a proinflammatory cytokine that mediates host defense against extracellular pathogens. Here, we compare these recently identified immune cells, reviewing what is known about their anatomical location, differentiation requirements, function, and potential involvement in host defense and autoimmunity. Finally, we discuss the challenges faced in furthering our understanding of the developmental relationships and role of NK and LTi-like cells in mucosal immune responses. Natural killer (NK) cells are innate lymphocytes that provide first-line defense against a range of viruses and tumors, typically functioning through two major mechanisms: (1) lysis of infected cells through release of perforin and granzymes or expression of death receptor ligands; (2) activation of other immune cell types through secretion of interferon (IFN)-γ and other cytokines. NK cell-mediated immunosurveillance relies on the expression of germline-encoded receptors, including Ly49s, KIRs, CD94-NKG2A and CD94-NKG2C dimers, NKG2D, 2B4, NKp46, NKp44, and NKp30, all of which possess well-defined ligand-binding repertoires (Lanier, 2008Lanier L.L. Up on the tightrope: natural killer cell activation and inhibition.Nat. Immunol. 2008; 9: 495-502Crossref PubMed Scopus (1055) Google Scholar). NK cells simultaneously express an array of receptors that are categorized as either activating or inhibitory. Several of the activating receptors recognize major histocompatibility complex (MHC) class I-like molecules that are encoded by pathogens and expressed on pathogen-infected cells (Scalzo and Yokoyama, 2008Scalzo A.A. Yokoyama W.M. Cmv1 and natural killer cell responses to murine cytomegalovirus infection.Curr. Top. Microbiol. Immunol. 2008; 321: 101-122Crossref PubMed Scopus (33) Google Scholar). Additional activating receptors recognize endogenous MHC class I-like molecules that are expressed only in the context of infection, DNA damage, or stress (Gasser and Raulet, 2006Gasser S. Raulet D. The DNA damage response, immunity and cancer.Semin. Cancer Biol. 2006; 16: 344-347Crossref PubMed Scopus (105) Google Scholar). Inhibitory receptors recognize MHC class I molecules and other cell-surface molecules, essentially setting the threshold for NK cell activation. If pathogen-infected or tumor cells lose expression of inhibitory ligands (a phenomenon known as "missing-self"), NK cells are released from inhibition and accordingly become capable of killing the affected cell (Karre, 2002Karre K. NK cells, MHC class I molecules and the missing self.Scand. J. Immunol. 2002; 55: 221-228Crossref PubMed Scopus (219) Google Scholar). Therefore, triggering of NK cell effector functions is the result of the integration of multiple activating and inhibitory signals (Bryceson and Long, 2008Bryceson Y.T. Long E.O. Line of attack: NK cell specificity and integration of signals.Curr. Opin. Immunol. 2008; 20: 344-352Crossref PubMed Scopus (151) Google Scholar). The magnitude of NK cell responses against infected or malignant cells is also dependent on alarm signals, which are released by sentinel immune cells, including dendritic cells (DCs), macrophages, and plasmacytoid DCs, as well as pathogen-infected tissues (Biron, 2001Biron C.A. Interferons alpha and beta as immune regulators–a new look.Immunity. 2001; 14: 661-664Abstract Full Text Full Text PDF PubMed Scopus (590) Google Scholar). These signals include type I IFNs (i.e., IFN-α and IFN-β), IL-12, IL-18, and IL-15, all of which enhance the lytic potential of NK cells and their ability to produce IFN-γ. Initially, human NK cells were classified into two subsets, on the basis of the degree of expression of the adhesion molecule CD56 (Caligiuri, 2008Caligiuri M.A. Human natural killer cells.Blood. 2008; 112: 461-469Crossref PubMed Scopus (1166) Google Scholar). CD56dim NK cells represent the vast majority of blood NK cells but are rare in the lymph nodes, whereas CD56bright NK cells are predominant in secondary lymphoid tissues such as lymph nodes and tonsils. CD56bright and CD56dim NK cells display distinct repertoires of inhibitory and activating receptors, utilize disparate adhesion molecules and chemokine receptors for homing, respond differently to IL-2, and, most importantly, demonstrate unique effector functions. Whereas CD56bright NK cells preferentially secrete IFN-γ, CD56dim NK cells are almost exclusively cytotoxic. Recent studies have proposed that these subsets represent two sequential stages of NK cell development, such that CD56bright cells are precursors of CD56dim cells, which represent the most differentiated and mature NK cell type (Freud and Caligiuri, 2006Freud A.G. Caligiuri M.A. Human natural killer cell development.Immunol. Rev. 2006; 214: 56-72Crossref PubMed Scopus (329) Google Scholar). Distinct stages of NK cell maturation can be also distinguished in the mouse, on the basis of the expression of CD11b and CD27 and the progressive acquisition of Ly49 receptors and effector functions (Hayakawa et al., 2006Hayakawa Y. Huntington N.D. Nutt S.L. Smyth M.J. Functional subsets of mouse natural killer cells.Immunol. Rev. 2006; 214: 47-55Crossref PubMed Scopus (182) Google Scholar). CD11bloCD27hi NK cells are immature cells preferentially located in bone marrow. CD11bhiCD27hi NK cells, present in the spleen, liver, and lymph nodes, are mature cells that secrete IFN-γ and are highly cytolytic. CD11bhiCD27lo NK cells have limited lytic capability, reside mainly in peripheral tissues such as the lungs, and may represent senescent cells. Developmental origin also contributes to murine NK cell diversity. In addition to classical bone-marrow-derived NK cells, NK cells with thymic origin have recently been recognized (Di Santo, 2008Di Santo J.P. Functionally distinct NK-cell subsets: developmental origins and biological implications.Eur. J. Immunol. 2008; 38: 2948-2951Crossref PubMed Scopus (55) Google Scholar). These cells express the α subunit of the receptor for IL-7 (IL-7Rα or CD127), CD69, and the transcription factor GATA3, and they preferentially home to the lymph nodes. NK cell diversity also depends on anatomical location. During pregnancy, both the human and murine placentas house unique subsets of NK cells that contribute to successful implant and function of the placenta by secreting angiogenetic factors, such as vascular endothelial growth factor (VEGF) (Croy et al., 2003Croy B.A. He H. Esadeg S. Wei Q. McCartney D. Zhang J. Borzychowski A. Ashkar A.A. Black G.P. Evans S.S. et al.Uterine natural killer cells: insights into their cellular and molecular biology from mouse modelling.Reproduction. 2003; 126: 149-160Crossref PubMed Scopus (173) Google Scholar, Manaster and Mandelboim, 2008Manaster I. Mandelboim O. The unique properties of human NK cells in the uterine mucosa.Placenta. 2008; 29: S60-S66Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). However, until now, little attention has been paid to NK cell diversity in the mucosae. A few studies have investigated murine NK cells in the lamina propria of the gut and tonsils, with reported functions similar to those of classical NK cells (Chinen et al., 2007Chinen H. Matsuoka K. Sato T. Kamada N. Okamoto S. Hisamatsu T. Kobayashi T. Hasegawa H. Sugita A. Kinjo F. et al.Lamina propria c-kit+ immune precursors reside in human adult intestine and differentiate into natural killer cells.Gastroenterology. 2007; 133: 559-573Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, Munz, 2008Munz C. Non-cytotoxic protection by human NK cells in mucosal secondary lymphoid tissues.Eur. J. Immunol. 2008; 38: 2946-2948Crossref PubMed Scopus (15) Google Scholar). More recently, however, a string of papers has emerged, detailing an unexpected diversification of NK cell function in the gut mucosa (Figure 1). In one study, analysis of human tonsils and Peyer's Patches (PPs) revealed an NK cell subset expressing the receptor NKp44, a marker that is absent on circulating NK cells (Cella et al., 2009Cella M. Fuchs A. Vermi W. Facchetti F. Otero K. Lennerz J.K. Doherty J.M. Mills J.C. Colonna M. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity.Nature. 2009; 457: 722-725Crossref PubMed Scopus (917) Google Scholar)(Table 1). NKp44+ cells are predominantly found in the mucosal areas covering the lymphoid aggregates (Figure 1). Consistent with their mucosal localization, NKp44+ cells express the chemokine receptor CCR6, which promotes leukocyte homing to the gut mucosa (Williams, 2006Williams I.R. CCR6 and CCL20: partners in intestinal immunity and lymphorganogenesis.Ann. N Y Acad. Sci. 2006; 1072: 52-61Crossref PubMed Scopus (121) Google Scholar). In addition, NKp44+ cells secrete CCL20, the ligand for CCR6, suggesting that these NK cells can promote their own accumulation. Transcriptional and functional profiles reveal that mucosal NKp44+ cells are not proficient at typical NK cell functions such as release of perforin and IFN-γ. Instead, NKp44+ cells isolated from the mucosae produce IL-22. IL-22 is a member of the family of IL-10-related cytokines, which protects the epithelial cell barrier in the gut and other mucosal surfaces from pathogens (Aujla and Kolls, 2009Aujla S.J. Kolls J.K. IL-22: a critical mediator in mucosal host defense.J. Mol. Med. 2009; 87: 451-454Crossref PubMed Scopus (128) Google Scholar, Kotenko, 2002Kotenko S.V. The family of IL-10-related cytokines and their receptors: related, but to what extent?.Cytokine Growth Factor Rev. 2002; 13: 223-240Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, Wolk and Sabat, 2006Wolk K. Sabat R. 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IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis.J. Clin. Invest. 2008; 118: 534-544PubMed Google Scholar). In addition, IL-22 induces hepatocytes to secrete acute phase proteins such as serum amyloid A and LPS-binding protein (Dumoutier et al., 2000Dumoutier L. Van Roost E. Colau D. Renauld J.C. Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor.Proc. Natl. Acad. Sci. USA. 2000; 97: 10144-10149Crossref PubMed Scopus (312) Google Scholar, Wolk et al., 2007Wolk K. Witte E. Hoffmann U. Doecke W.D. Endesfelder S. Asadullah K. Sterry W. Volk H.D. Wittig B.M. Sabat R. IL-22 induces lipopolysaccharide-binding protein in hepatocytes: a potential systemic role of IL-22 in Crohn's disease.J. Immunol. 2007; 178: 5973-5981PubMed Google Scholar) and protects the liver in a mouse model of acute hepatitis (Zenewicz et al., 2007Zenewicz L.A. Yancopoulos G.D. 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However, this pathogenic effect is likely to reflect dysregulated duration and/or amount of IL-22 secretion. NKp44+ NK cells also produce IL-26 and the leukemia inhibitory factor (LIF). IL-26 is another IL-10-related cytokine that is present only in humans. The receptor for IL-26 is predominantly expressed on epithelial cells, and therefore IL-26, like IL-22, acts mainly on epithelial cells, inducing STAT3 and STAT3-dependent pathways that promote cutaneous and mucosal immunity (Hor et al., 2004Hor S. Pirzer H. Dumoutier L. Bauer F. Wittmann S. Sticht H. Renauld J.C. de Waal Malefyt R. Fickenscher H. The T-cell lymphokine interleukin-26 targets epithelial cells through the interleukin-20 receptor 1 and interleukin-10 receptor 2 chains.J. Biol. Chem. 2004; 279: 33343-33351Crossref PubMed Scopus (106) Google Scholar, Nagalakshmi et al., 2004aNagalakshmi M.L. Murphy E. McClanahan T. de Waal Malefyt R. Expression patterns of IL-10 ligand and receptor gene families provide leads for biological characterization.Int. Immunopharmacol. 2004; 4: 577-592Crossref PubMed Scopus (117) Google Scholar). The LIF activates STAT3 and, among other functions, has been reported to protect the lung alveolar epithelium in a model of bacterial infection (Quinton et al., 2008Quinton L.J. Jones M.R. Robson B.E. Simms B.T. Whitsett J.A. Mizgerd J.P. Alveolar epithelial STAT3, IL-6 family cytokines, and host defense during Escherichia coli pneumonia.Am. J. Respir. Cell Mol. Biol. 2008; 38: 699-706Crossref PubMed Scopus (83) Google Scholar). Remarkably, although IL-22 and IL-26 are frequently produced together with IL-17 by CD4+ T helper 17 (Th17) cells (Chung et al., 2006Chung Y. Yang X. Chang S.H. Ma L. Tian Q. Dong C. Expression and regulation of IL-22 in the IL-17-producing CD4+ T lymphocytes.Cell Res. 2006; 16: 902-907Crossref PubMed Scopus (182) Google Scholar, Liang et al., 2006Liang S.C. Tan X.Y. Luxenberg D.P. Karim R. Dunussi-Joannopoulos K. Collins M. Fouser L.A. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides.J. Exp. Med. 2006; 203: 2271-2279Crossref PubMed Scopus (1690) Google Scholar, Wilson et al., 2007Wilson N.J. Boniface K. Chan J.R. McKenzie B.S. Blumenschein W.M. Mattson J.D. Basham B. Smith K. Chen T. Morel F. et al.Development, cytokine profile and function of human interleukin 17-producing helper T cells.Nat. Immunol. 2007; 8: 950-957Crossref PubMed Scopus (1552) Google Scholar), NKp44+ cells do not produce IL-17 (Cella et al., 2009Cella M. Fuchs A. Vermi W. Facchetti F. Otero K. Lennerz J.K. Doherty J.M. Mills J.C. Colonna M. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity.Nature. 2009; 457: 722-725Crossref PubMed Scopus (917) Google Scholar). Corresponding analysis of NK cells in the murine gut yielded very similar findings (Table 1) (Cella et al., 2009Cella M. Fuchs A. Vermi W. Facchetti F. Otero K. Lennerz J.K. Doherty J.M. Mills J.C. Colonna M. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity.Nature. 2009; 457: 722-725Crossref PubMed Scopus (917) Google Scholar, Luci et al., 2009Luci C. Reynders A. Ivanov I.I. Cognet C. Chiche L. Chasson L. Hardwigsen J. Anguiano E. Banchereau J. Chaussabel D. et al.Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin.Nat. Immunol. 2009; 10: 75-82Crossref PubMed Scopus (433) Google Scholar, Sanos et al., 2009Sanos S.L. Bui V.L. Mortha A. Oberle K. Heners C. Johner C. Diefenbach A. RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells.Nat. Immunol. 2009; 10: 83-91Crossref PubMed Scopus (612) Google Scholar, Satoh-Takayama et al., 2008Satoh-Takayama N. Vosshenrich C.A. Lesjean-Pottier S. Sawa S. Lochner M. Rattis F. Mention J.J. Thiam K. Cerf-Bensussan N. Mandelboim O. et al.Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense.Immunity. 2008; 29: 958-970Abstract Full Text Full Text PDF PubMed Scopus (788) Google Scholar). Analysis of NK cells in the lamina propria and intraepithelial surfaces of the mouse small intestine with the use of multiple markers such as NKp46, NK1.1, CD127, and c-Kit (not NKp44, which is only expressed in humans) revealed substantial heterogeneity. A subpopulation of NKp46+ cells express CD127 (IL-7Rα) and c-Kit, lack Ly49 receptors, and are poor producer of perforin and IFN-γ (Figure 1). Interestingly, the classical NK cell marker NK1.1 is expressed only on a small subset of these cells. Functional characterization of NKp46+CD127+c-Kit+NK1.1− and NKp46+CD127+c-Kit+NK1+ cells confirmed expression of the IL-22 transcript (Luci et al., 2009Luci C. Reynders A. Ivanov I.I. Cognet C. Chiche L. Chasson L. Hardwigsen J. Anguiano E. Banchereau J. Chaussabel D. et al.Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin.Nat. Immunol. 2009; 10: 75-82Crossref PubMed Scopus (433) Google Scholar, Satoh-Takayama et al., 2008Satoh-Takayama N. Vosshenrich C.A. Lesjean-Pottier S. Sawa S. Lochner M. Rattis F. Mention J.J. Thiam K. Cerf-Bensussan N. Mandelboim O. et al.Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense.Immunity. 2008; 29: 958-970Abstract Full Text Full Text PDF PubMed Scopus (788) Google Scholar) and protein (Cella et al., 2009Cella M. Fuchs A. Vermi W. Facchetti F. Otero K. Lennerz J.K. Doherty J.M. Mills J.C. Colonna M. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity.Nature. 2009; 457: 722-725Crossref PubMed Scopus (917) Google Scholar, Sanos et al., 2009Sanos S.L. Bui V.L. Mortha A. Oberle K. Heners C. Johner C. Diefenbach A. RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells.Nat. Immunol. 2009; 10: 83-91Crossref PubMed Scopus (612) Google Scholar), comparable to human NKp44+ cells (Figure 1). Moreover, NKp46+CD127+c-Kit+NK1.1− and NKp46+CD127+c-Kit+NK1.1+ cells express the GM-CSF transcript (Satoh-Takayama et al., 2008Satoh-Takayama N. Vosshenrich C.A. Lesjean-Pottier S. Sawa S. Lochner M. Rattis F. Mention J.J. Thiam K. Cerf-Bensussan N. Mandelboim O. et al.Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense.Immunity. 2008; 29: 958-970Abstract Full Text Full Text PDF PubMed Scopus (788) Google Scholar) (Table 1). A second subpopulation of NKp46+ cells lacks CD127 and bears features typical of classical NK cells, such as coexpression of NK1.1, various Ly49 receptors, perforin, and IFN-γ. Collectively, these studies demonstrate the conservation of a unique NK cell subset that specializes in IL-22 secretion in both humans and mice.Table 1Characteristics of IL-22-Producing NK Cells and LTi-like Cells in Human and MouseNamePhenotypeCytokinesLocationChemokine Receptors and ChemokinesTranscription FactorsGenetic Mutations Affecting Development or FunctionHumanNK-22CD3-CD56+NKp44+c-Kit+IL-22tonsil, PPsCCR6, CCL20RORγt, AHR, RORα, IRF4NK stage 3 (iNK)CD34−CD56−NKp44+ c-Kit+CD94−IL-22tonsilLTiCD4−lin−CD127+CD45int c-Kit+CD161+CD7+IL-17, IL-22fetal mesentery, MLNs, PLNsCCR7RORγt, TCF3, Id2LTi-like (iNK?)CD34−CD56+CD127+c-Kit+IL-17, IL-22fetal MLNs, postnatal tonsilMouseRORγt+NKp46+NK1.1−CD3−CD127+c-Kit+CD122lo CD11b−CD27−Ly49A/D− NKG2DloCD94−IL-22, GM-CSFPPs, LP, IELs, CPsCCR7, CXCL2RORγt, RORαRorcGFP/GFP, Rag2−/−Il2rc−/−RORγt+NKp46+NK1.1+CD3−CD127+c-Kit+CD122loCD11b−CD27−/+ Ly49A/D−NKG2D+CD94+IL-22, GM-CSFPPs, LP, IELs, CPsRORγt, Id2Rag2−/−Il2rb−/−, Il15−/−, Rag2−/−Il2rc−/−LTi-likeCD4+CD3−NK1.1−CD11b− Gr1−CD11c−B220−IL-17, IL-22Spleen, LPCCR6, CXCR5, CCR7RORγt, AHR, STAT3Rag2−/−Il2rc−/−, Stat3fl/flMMTVCreAbbreviations are as follows: PPs, Peyer's Patches; MLNs, mesenteric lymph nodes; PLNs, peripheral lymph nodes; LP, intestinal lamina propria; IELs, intraepithelial lymphocytes; CPs, cryptopatches. Open table in a new tab Abbreviations are as follows: PPs, Peyer's Patches; MLNs, mesenteric lymph nodes; PLNs, peripheral lymph nodes; LP, intestinal lamina propria; IELs, intraepithelial lymphocytes; CPs, cryptopatches. Functional differentiation of T cells and NK cells relies on unique transcription factors that induce the production of distinctive cytokines that direct immune responses (Weaver and Murphy, 2007Weaver C.T. Murphy K.M. T-cell subsets: the more the merrier.Curr. Biol. 2007; 17: R61-R63Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar; Di Santo, 2008Di Santo J.P. Functionally distinct NK-cell subsets: developmental origins and biological implications.Eur. J. Immunol. 2008; 38: 2948-2951Crossref PubMed Scopus (55) Google Scholar). Accordingly, a major issue that arises in the study of NK cell subsets is identifying the transcription factors responsible for their differentiation. Which transcription factors selectively drive the differentiation of IL-22-producing NK cells? Initial analysis of this NK cell subset has focused on the role of the retinoic acid receptor-related orphan receptor gamma t (RORγt) for at least two reasons. First, RORγt is essential for differentiation of CD4+ Th17 cells (Ivanov et al., 2007Ivanov I.I. Zhou L. Littman D.R. Transcriptional regulation of Th17 cell differentiation.Semin. Immunol. 2007; 19: 409-417Crossref PubMed Scopus (348) Google Scholar), which frequently produce IL-22 (Chung et al., 2006Chung Y. Yang X. Chang S.H. Ma L. Tian Q. Dong C. Expression and regulation of IL-22 in the IL-17-producing CD4+ T lymphocytes.Cell Res. 2006; 16: 902-907Crossref PubMed Scopus (182) Google Scholar, Liang et al., 2006Liang S.C. Tan X.Y. Luxenberg D.P. Karim R. Dunussi-Joannopoulos K. Collins M. Fouser L.A. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides.J. Exp. Med. 2006; 203: 2271-2279Crossref PubMed Scopus (1690) Google Scholar, Wilson et al., 2007Wilson N.J. Boniface K. Chan J.R. McKenzie B.S. Blumenschein W.M. Mattson J.D. Basham B. Smith K. Chen T. Morel F. et al.Development, cytokine profile and function of human interleukin 17-producing helper T cells.Nat. Immunol. 2007; 8: 950-957Crossref PubMed Scopus (1552) Google Scholar). Second, RORγt is expressed in lymphoid tissue inducer (LTi) cells, which somewhat resemble IL-22-producing NK cells phenotypically for the expression of CD127 and c-Kit and are located in similar areas in the gut of adult mice (Eberl and Littman, 2003Eberl G. Littman D.R. The role of the nuclear hormone receptor RORgammat in the development of lymph nodes and Peyer's patches.Immunol. Rev. 2003; 195: 81-90Crossref PubMed Scopus (155) Google Scholar). Indeed, IL-22-producing NK cells from both mice (Luci et al., 2009Luci C. Reynders A. Ivanov I.I. Cognet C. Chiche L. Chasson L. Hardwigsen J. Anguiano E. 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