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• W2155997615 abstract "Natural killer (NK) cells are innate lymphocytes with spontaneous antitumor activity, and they produce interferon-γ (IFN-γ) that primes immune responses. Whereas T helper cell subsets differentiate from naive T cells via specific transcription factors, evidence for NK cell diversification is limited. In this report, we characterized intestinal lymphocytes expressing the NK cell natural cytotoxicity receptor NKp46. Gut NKp46+ cells were distinguished from classical NK cells by limited IFN-γ production and absence of perforin, whereas several subsets expressed the nuclear hormone receptor retinoic acid receptor-related orphan receptor t (RORγt) and interleukin-22 (IL-22). Intestinal NKp46+IL-22+ cells were generated via a local process that was conditioned by commensal bacteria and required RORγt. Mice lacking IL-22-producing NKp46+ cells showed heightened susceptibility to the pathogen Citrobacter rodentium, consistent with a role for intestinal NKp46+ cells in immune protection. RORγt-driven diversification of intestinal NKp46+ cells thereby specifies an innate cellular defense mechanism that operates at mucosal surfaces. Natural killer (NK) cells are innate lymphocytes with spontaneous antitumor activity, and they produce interferon-γ (IFN-γ) that primes immune responses. Whereas T helper cell subsets differentiate from naive T cells via specific transcription factors, evidence for NK cell diversification is limited. In this report, we characterized intestinal lymphocytes expressing the NK cell natural cytotoxicity receptor NKp46. Gut NKp46+ cells were distinguished from classical NK cells by limited IFN-γ production and absence of perforin, whereas several subsets expressed the nuclear hormone receptor retinoic acid receptor-related orphan receptor t (RORγt) and interleukin-22 (IL-22). Intestinal NKp46+IL-22+ cells were generated via a local process that was conditioned by commensal bacteria and required RORγt. Mice lacking IL-22-producing NKp46+ cells showed heightened susceptibility to the pathogen Citrobacter rodentium, consistent with a role for intestinal NKp46+ cells in immune protection. RORγt-driven diversification of intestinal NKp46+ cells thereby specifies an innate cellular defense mechanism that operates at mucosal surfaces. Natural killer (NK) cells develop from hematopoietic stem cells under the influence of soluble factors and stromal cell interactions provided in the bone marrow (BM) and thymic microenvironments (Di Santo, 2006Di Santo J.P. Natural killer cell developmental pathways: A question of balance.Annu. Rev. Immunol. 2006; 24: 257-286Crossref PubMed Scopus (337) Google Scholar). The process of NK cell maturation involves the sequential acquisition of cell-surface receptors that provide either activating or inhibitory signals (Lanier, 2005Lanier L.L. NK cell recognition.Annu. Rev. Immunol. 2005; 23: 225-274Crossref PubMed Scopus (2108) Google Scholar, Raulet et al., 2001Raulet D.H. Vance R.E. McMahon C.W. Regulation of the natural killer cell receptor repertoire.Annu. Rev. Immunol. 2001; 19: 291-330Crossref PubMed Scopus (430) Google Scholar). NK cells are “educated” toward host major histocompatibility complex (MHC) class I molecules as their concomitantly expressed inhibitory receptors (of the NKG2 and Ly49 families) specific for MHC class I molecules are tested (Gasser and Raulet, 2006Gasser S. Raulet D.H. Activation and self-tolerance of natural killer cells.Immunol. Rev. 2006; 214: 130-142Crossref PubMed Scopus (166) Google Scholar). NK cells that pass this developmental checkpoint are considered “competent” and acquire diverse functional capacities, including granule-mediated cytotoxicity and prompt chemokine and cytokine production (predominantly of interferon-γ [IFN-γ] and tumor necrosis factor-α [TNF-α]) (Yokoyama and Kim, 2006Yokoyama W.M. Kim S. Licensing of natural killer cells by self-major histocompatibility complex class I.Immunol. Rev. 2006; 214: 143-154Crossref PubMed Scopus (179) Google Scholar). BM and thymus-derived NK cells seed the peripheral lymphoid organs and primarily localize in the spleen, lymph node (LN), liver, and lung and in the uterus during gestation (Huntington et al., 2007Huntington N.D. Vosshenrich C.A. Di Santo J.P. Developmental pathways that generate natural-killer-cell diversity in mice and humans.Nat. Rev. Immunol. 2007; 7: 703-714Crossref PubMed Scopus (278) Google Scholar). NK cells perform critical functions during innate and adaptive immune responses, by virtue of their ability to eliminate virus-infected, transformed, or stressed cells and to recruit and amplify inflammatory responses (Trinchieri, 1995Trinchieri G. Natural killer cells wear different hats: Effector cells of innate resistance and regulatory cells of adaptive immunity and of hematopoiesis.Semin. Immunol. 1995; 7: 83-88Crossref PubMed Scopus (126) Google Scholar). NK cells have been long considered as a homogeneous population of cytotoxic and cytokine-producing cells. As such, NK cells may be predicted to perform stereotyped roles during the immune response, with little flexibility in their biological functions. In contrast, several different T helper (Th) cell subsets (Th1, Th2, and Th17) differentiate from naive T cells after antigen activation in a process that is guided by transcription factors and results in the generation of distinct effector T cells with specialized functions (Ho and Glimcher, 2002Ho I.C. Glimcher L.H. Transcription: Tantalizing times for T cells.Cell. 2002; 109: S109-S120Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, Weaver et al., 2007Weaver C.T. Hatton R.D. Mangan P.R. Harrington L.E. IL-17 family cytokines and the expanding diversity of effector T cell lineages.Annu. Rev. Immunol. 2007; 25: 821-852Crossref PubMed Scopus (1470) Google Scholar). In contrast, evidence for a similar level of functional diversification in the NK cell lineage is limited. Early studies identified phenotypically distinct human NK cell subsets (Lanier et al., 1986Lanier L.L. Le A.M. Civin C.I. Loken M.R. Phillips J.H. The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes.J. Immunol. 1986; 136: 4480-4486PubMed Google Scholar) that were subsequently shown to have different tissue localizations and functional properties (Fehniger et al., 2003Fehniger T.A. Cooper M.A. Nuovo G.J. Cella M. Facchetti F. Colonna M. Caligiuri M.A. CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: A potential new link between adaptive and innate immunity.Blood. 2003; 101: 3052-3057Crossref PubMed Scopus (623) Google Scholar, Ferlazzo et al., 2004Ferlazzo G. Thomas D. Lin S.L. Goodman K. Morandi B. Muller W.A. Moretta A. Munz C. The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic.J. Immunol. 2004; 172: 1455-1462PubMed Google Scholar). Recent observations in the mouse have confirmed the existence of distinct NK cell subsets (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, Veinotte et al., 2008Veinotte L.L. Halim T.Y. Takei F. Unique subset of natural killer cells develops from progenitors in lymph node.Blood. 2008; 111: 4201-4208Crossref PubMed Scopus (26) Google Scholar, Vosshenrich et al., 2006Vosshenrich C.A. Garcia-Ojeda M.E. Samson-Villeger S.I. Pasqualetto V. Enault L. Richard-Le Goff O. Corcuff E. Guy-Grand D. Rocha B. Cumano A. et al.A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127.Nat. Immunol. 2006; 7: 1217-1224Crossref PubMed Scopus (357) Google Scholar). NK cell subsets may be generated as a consequence of programming via transcription factors or may represent different stages of an ongoing process of NK cell differentiation, in which maturing NK cells exhibit unique functional capacities. The mechanisms that control acquisition of NK cell effector functions are not fully understood, but they may include signals derived from the environment that could be altered during infection. One example is the recent report describing interleukin-10 (IL-10) production by activated NK cells in the context of chronic Leishmania infection (Maroof et al., 2008Maroof A. Beattie L. Zubairi S. Svensson M. Stager S. Kaye P.M. Posttranscriptional regulation of IL-10 gene expression allows natural killer cells to express immunoregulatory function.Immunity. 2008; 29: 295-305Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). Collectively, these results challenge the general notion that NK cells function in a homogeneous fashion as proinflammatory killer cells. In the intestinal tract, a coordinated system of hematopoietic and nonhematopoietic cell types synergize to provide immune defense against potential ingested pathogens (reviewed in Artis, 2008Artis D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut.Nat. Rev. Immunol. 2008; 8: 411-420Crossref PubMed Scopus (738) Google Scholar). A single cell layer of epithelial cells separates the gut lumen harboring the commensal flora and food-born pathogenic antigens from the body. The protective function of epithelial cells includes not only a primary physical barrier, but also an immunoregulatory role via the secretion of antimicrobial peptides, cytokines, and chemokines that recruit hematopoietic cells. Additional sensors include intestinal dendritic cells (DCs) that extend transepithelial dendrites into the intestinal lumen and sample its contents for signs of infection. Specialized M cells provide a “pump” that feeds Peyers' patch DCs with gut antigens to initiate adaptive immune responses that are tuned toward immunoglobin A secretion. Whereas NK cells have been documented in the intestinal mucosa (Leon et al., 2003Leon F. Roldan E. Sanchez L. Camarero C. Bootello A. Roy G. Human small-intestinal epithelium contains functional natural killer lymphocytes.Gastroenterology. 2003; 125: 345-356Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, Tagliabue et al., 1982Tagliabue A. Befus A.D. Clark D.A. Bienenstock J. Characteristics of natural killer cells in the murine intestinal epithelium and lamina propria.J. Exp. Med. 1982; 155: 1785-1796Crossref PubMed Scopus (158) Google Scholar), the developmental pathways that generate gut NK cells and the biological roles for intestinal NK cells in mucosal immunity are not understood. NK cells, by virtue of their rapid cytokine response, might play an important role in intestinal immunity by interfacing with intestinal DCs to regulate the orchestration of immune responses. Alternatively, NK cells may eliminate stressed or infected target cells and contribute to epithelial cell homeostasis. In this study, we characterized distinct subsets of intestinal lymphocytes that expressed the natural cytotoxicity receptor NKp46. We used this molecule as a starting point because NKp46 has been shown to be highly and specifically expressed in NK cells (Biassoni et al., 1999Biassoni R. Pessino A. Bottino C. Pende D. Moretta L. Moretta A. The murine homologue of the human NKp46, a triggering receptor involved in the induction of natural cytotoxicity.Eur. J. Immunol. 1999; 29: 1014-1020Crossref PubMed Scopus (131) Google Scholar, Sivori et al., 1997Sivori S. Vitale M. Morelli L. Sanseverino L. Augugliaro R. Bottino C. Moretta L. Moretta A. p46, a novel natural killer cell-specific surface molecule that mediates cell activation.J. Exp. Med. 1997; 186: 1129-1136Crossref PubMed Scopus (397) Google Scholar). Surprisingly, a substantial subset of NKp46+ cells in the intestine lacked perforin and did not transcribe IFN-γ, and they thus bore little functional resemblance to classical NK cells. In contrast, these cells expressed the nuclear hormone receptor retinoic acid receptor-related orphan receptor gamma t (RORγt) and IL-22 in response to local microenvironmental signals and were involved in immune defense against the pathogen Citrobacter rodentium. Our results provide evidence for an intestinal “niche” that conditions the differentiation of diverse NKp46+ cell subsets that appear to play a role in mucosal immunity. NK cells from several species have been shown to specifically express the natural cytotoxicity receptor NKp46 (encoded by the Ncr1 locus) (Biassoni et al., 1999Biassoni R. Pessino A. Bottino C. Pende D. Moretta L. Moretta A. The murine homologue of the human NKp46, a triggering receptor involved in the induction of natural cytotoxicity.Eur. J. Immunol. 1999; 29: 1014-1020Crossref PubMed Scopus (131) Google Scholar, Gazit et al., 2006Gazit R. Gruda R. Elboim M. Arnon T.I. Katz G. Achdout H. Hanna J. Qimron U. Landau G. Greenbaum E. et al.Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1.Nat. Immunol. 2006; 7: 517-523Crossref PubMed Scopus (415) Google Scholar, Sivori et al., 1997Sivori S. Vitale M. Morelli L. Sanseverino L. Augugliaro R. Bottino C. Moretta L. Moretta A. p46, a novel natural killer cell-specific surface molecule that mediates cell activation.J. Exp. Med. 1997; 186: 1129-1136Crossref PubMed Scopus (397) Google Scholar, Walzer et al., 2007Walzer T. Blery M. Chaix J. Fuseri N. Chasson L. Robbins S.H. Jaeger S. Andre P. Gauthier L. Daniel L. et al.Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46.Proc. Natl. Acad. Sci. USA. 2007; 104: 3384-3389Crossref PubMed Scopus (329) Google Scholar). In order to facilitate identification of NKp46+ cells, we studied Ncr1GFP/+ mice on the C57BL/6 background that harbor a green fluorescent protein (GFP) reporter driven by the Ncr1 promoter (Gazit et al., 2006Gazit R. Gruda R. Elboim M. Arnon T.I. Katz G. Achdout H. Hanna J. Qimron U. Landau G. Greenbaum E. et al.Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1.Nat. Immunol. 2006; 7: 517-523Crossref PubMed Scopus (415) Google Scholar). As expected, CD3−NKp46+ cells were present in BM, spleen, thymus, liver, and lymph nodes (Figure 1A and data not shown). CD3−NKp46+ cells were also clearly identified as a subset of lamina propria lymphocytes (LPLs) and intraepithelial lymphocytes (IELs) in the small and large intestines of Ncr1GFP/+ mice (Figure 1A). These cells showed typical lymphocyte morphology with scant cytoplasmic differentiation and an overall appearance similar to splenic NK cells (data not shown). Intestinal CD3−NKp46+ cells were dispersed throughout the lamina propria, were more rarely found in the intraepithelial position, and were essentially absent from the region of the intestinal crypts (Figure 1B and data not shown). Because CD127 (IL-7Rα) expression has been observed on thymic NK1.1+ cells and a subset of lymph node NK cells (Veinotte et al., 2008Veinotte L.L. Halim T.Y. Takei F. Unique subset of natural killer cells develops from progenitors in lymph node.Blood. 2008; 111: 4201-4208Crossref PubMed Scopus (26) Google Scholar, Vosshenrich et al., 2006Vosshenrich C.A. Garcia-Ojeda M.E. Samson-Villeger S.I. Pasqualetto V. Enault L. Richard-Le Goff O. Corcuff E. Guy-Grand D. Rocha B. Cumano A. et al.A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127.Nat. Immunol. 2006; 7: 1217-1224Crossref PubMed Scopus (357) Google Scholar), we used CD127 and the prototypic NK cell marker NK1.1 (recognizing the C-lectin NKR-P1C) to further characterize the gut CD3−NKp46+ LPL and IEL populations (Figure 1C). Splenic CD3−NKp46+ cells were predominantly NK1.1+CD127− and uniformly expressed CD122 (IL-2Rβ), CD11b, CD49b (DX5), the activating receptors NKG2D and CD16, and a “repertoire” of MHC-specific CD94 and Ly49 receptors (Figure 1C and data not shown). We noticed that intestinal CD3−NKp46+ cells were far more heterogeneous, and we could identify three subsets differentially expressing CD127 and NK1.1 (Figure 1C). The first subset was CD127+NK1.1− and expressed some NK cell markers (including CD224 [2B4] and low amounts of CD122 and NKG2D), but it was negative for CD11b, CD49b, CD94, and Ly49A and Ly49D (Figure 1C). Two NK1.1+ cell subsets (CD127+ and CD127−) appear more like splenic NK cells with expression of NKG2D, CD94, and CD224 but relatively lower densities of CD49b, CD11b, CD27, and Ly49 family members (Figure 1C and data not shown). These different CD3−NKp46+ cell subsets were also numerous in the small intestine IEL compartment and large intestine lamina propria (Figure S1 available online). Together, these results reveal substantial phenotypic heterogeneity in gut CD3−NKp46+ cells. NK cells employ several mechanisms to eliminate stressed or transformed target cells, including granule-mediated cytotoxicity and activation of Fas-associated protein with death domain (FADD)-linked death receptors (Smyth et al., 2002Smyth M.J. Hayakawa Y. Takeda K. Yagita H. New aspects of natural-killer-cell surveillance and therapy of cancer.Nat. Rev. Cancer. 2002; 2: 850-861Crossref PubMed Scopus (547) Google Scholar). We therefore assessed whether intestinal NKp46+ cells showed these typical NK cell cytotoxicity pathways. Optimal granule-mediated cytotoxicity requires the coordinated activity of the pore-forming protein perforin and a family of granzyme serine proteases (Kagi et al., 1994Kagi D. Ledermann B. Burki K. Seiler P. Odermatt B. Olsen K.J. Podack E.R. Zinkernagel R.M. Hengartner H. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice.Nature. 1994; 369: 31-37Crossref PubMed Scopus (1492) Google Scholar, Shresta et al., 1995Shresta S. MacIvor D.M. Heusel J.W. Russell J.H. Ley T.J. Natural killer and lymphokine-activated killer cells require granzyme B for the rapid induction of apoptosis in susceptible target cells.Proc. Natl. Acad. Sci. USA. 1995; 92: 5679-5683Crossref PubMed Scopus (201) Google Scholar, Smyth et al., 2005Smyth M.J. Cretney E. Kelly J.M. Westwood J.A. Street S.E. Yagita H. Takeda K. van Dommelen S.L. Degli-Esposti M.A. Hayakawa Y. Activation of NK cell cytotoxicity.Mol. Immunol. 2005; 42: 501-510Crossref PubMed Scopus (414) Google Scholar). To assess the expression of perforin by gut NK cells, we used mice that harbor a yellow fluorescent protein (YFP) reporter gene driven by the perforin promoter (PfpYFP/+ mice). As expected, splenic NK cells from PfpYFP/+ mice uniformly expressed YFP (Figure 2A). In contrast, most intestinal CD3−NKp46+ cells from these mice lacked perforin expression, although a small subset of NK1.1+CD127− cells showed weak YFP expression (Figure 2A). NK cells can induce apoptosis in target cells through activation of FADD-linked death receptors such as TRAIL-R and Fas. We found that intestinal CD3−NKp46+ cells were TRAIL− (Figure 2B), and only a minor population expressed FasL (Figure 2C). Thus, most intestinal CD3−NKp46+ cells lack the critical effector molecules required for cell-mediated cytotoxicity. NK cells have the capacity to rapidly secrete a variety of cytokines after activation. In humans and mice, NK cell subsets have been described that show enhanced cytokine production, in particular production of proinflammatory Th1 cell cytokines IFN-γ and TNF-α (Huntington et al., 2007Huntington N.D. Vosshenrich C.A. Di Santo J.P. Developmental pathways that generate natural-killer-cell diversity in mice and humans.Nat. Rev. Immunol. 2007; 7: 703-714Crossref PubMed Scopus (278) Google Scholar). In order to determine the capacity of intestinal NK cells to produce IFN-γ, we used mice that harbor a YFP reporter in the 3′-untranslated region of the Ifng locus (IfngYFP/+ mice) that can identify cells having the potential for rapid IFN-γ production because of a remodeled IFN-γ locus (Stetson et al., 2003Stetson D.B. Mohrs M. Reinhardt R.L. Baron J.L. Wang Z.E. Gapin L. Kronenberg M. Locksley R.M. Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function.J. Exp. Med. 2003; 198: 1069-1076Crossref PubMed Scopus (474) Google Scholar). We confirmed that splenic NK cells in IfngYFP/+ mice demonstrate high YFP expression (Figure 2D), consistent with their IFN-γ-producing potential (Figure 2E). In contrast, intestinal CD3−NKp46+ cell subsets showed distinct patterns of YFP expression, with most CD127+ cells appearing incompetent for IFN-γ production, whereas the CD127− subset had YFP expression similar to that of splenic NK cells. Collectively, these results indicated that most intestinal NKp46+ cells were functionally distinct from splenic NK cells. To gain more insight into the potential relationship of intestinal NKp46+ cells to known NK cell subsets and to help identify their potential effector functions, we compared their transcription factor (TF) profiles. Several TFs are critical for NK cell development in the BM and thymus (including Id2, GATA-3, PU.1, and Ikaros), whereas others modulate their differentiation into cytokine-producing killer cells (T-bet, GATA-3, IRF-2, MEF, and CEBP-γ) (Di Santo, 2006Di Santo J.P. Natural killer cell developmental pathways: A question of balance.Annu. Rev. Immunol. 2006; 24: 257-286Crossref PubMed Scopus (337) Google Scholar). CD3−NKp46+ cells, irrespective of their origin, expressed transcripts for Id2 but were negative for Foxp3 (Figure 3A and data not shown). Tbx21 (T-bet) expression was only observed in splenic NK cells, whereas Gata3 expression was similar in NK cells from the spleen and gut (Figure 3A). Strikingly, a subset of intestinal CD3−NKp46+ cells expressed the nuclear hormone receptor RORγt encoded by Rorc. We confirmed RORγt expression in intestinal NKp46+ cells by using recently described bacterial artificial chromosome (BAC) transgenic mice harboring a GFP reporter under the control of the Rorc promoter (Lochner et al., 2008Lochner M. Peduto L. Cherrier M. Sawa S. Langa F. Varona R. Riethmacher D. Si-Tahar M. Di Santo J.P. Eberl G. In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORgamma t+ T cells.J. Exp. Med. 2008; 205: 1381-1393Crossref PubMed Scopus (384) Google Scholar). In Rorc-GFP mice, GFP expression was found in intestinal NKp46+ cells expressing CD127 (both in the LPL and IEL), whereas NK1.1+ NK cells lacking CD127 (in the intestine or elsewhere) were essentially GFP− (Figure 3B). Interestingly, almost all CD127+NK1.1− cells were GFP+ compared with CD127+NK1.1+ cells that only harbored a fraction (approximately 40%) of RORγt+ cells (Figure 3B). Immunohistology confirmed that CD3−NKp46+RORγt+ cells were located primarily as scattered cells in the intestinal LP and were rare in the cryptopatches at the base of the villi (Figure 3C). We next assessed whether differential RORγt expression by intestinal NKp46+ cells had any impact on their functional properties. By comparing GFP expression with NK1.1 expression in Rorc-GFP mice, we could clearly identify NKp46+ cell subsets that expressed distinct amounts of RORγt (Figure 3D). NKp46+ cells expressing the highest amount of RORγt were essentially NK1.1− (and uniformly expressed CD127; Figure 3B). As such, this NKp46+CD127+NK1.1− cell subset may be related to the previously described RORγt+ lymphoid tissue inducer (LTi) cells known to orchestrate development of programmed secondary and induced tertiary intestinal lymphoid aggregates (Eberl and Littman, 2004Eberl G. Littman D.R. Thymic origin of intestinal alphabeta T cells revealed by fate mapping of RORgammat+ cells.Science. 2004; 305: 248-251Crossref PubMed Scopus (389) Google Scholar, Mebius, 2003Mebius R.E. Organogenesis of lymphoid tissues.Nat. Rev. Immunol. 2003; 3: 292-303Crossref PubMed Scopus (574) Google Scholar). LTi cells express CD4 and reside in cryptopatches, which are structures found between intestinal crypts (Eberl, 2007Eberl G. From induced to programmed lymphoid tissues: The long road to preempt pathogens.Trends Immunol. 2007; 28: 423-428Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, Ivanov et al., 2006aIvanov I.I. Diehl G.E. Littman D.R. Lymphoid tissue inducer cells in intestinal immunity.Curr. Top. Microbiol. Immunol. 2006; 308: 59-82Crossref PubMed Scopus (55) Google Scholar). Because NKp46+CD127+NK1.1− cells are CD4− (data not shown) and are not observed near the intestinal crypts (Figures 1B and 3C), they appear to differ from LTi cells that also express high amounts of RORγt (Eberl et al., 2004Eberl G. Marmon S. Sunshine M.J. Rennert P.D. Choi Y. Littman D.R. An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells.Nat. Immunol. 2004; 5: 64-73Crossref PubMed Scopus (738) Google Scholar). The developmental or functional relationship of the NKp46+RORγthi cells that we have identified to the previously described LTi cells is unclear. Nevertheless, NKp46 expression by RORγthi cells could caution against the use of this marker in a “universal definition” of NK cells (Walzer et al., 2007Walzer T. Blery M. Chaix J. Fuseri N. Chasson L. Robbins S.H. Jaeger S. Andre P. Gauthier L. Daniel L. et al.Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46.Proc. Natl. Acad. Sci. USA. 2007; 104: 3384-3389Crossref PubMed Scopus (329) Google Scholar). NKp46+ cells expressing intermediate amounts of RORγt were essentially NK1.1+ (Figure 3D) and coexpressed CD127 (Figure 3B), whereas NKp46+ cells that were RORγt− were essentially NK1.1+ (Figure 3D). Thus, two different NKp46+ populations of cells expressing different amounts of RORγt+ are present in the gut. RORγt is an essential orchestrator of the Th17 cell pathway (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). We therefore compared steady-state expression profiles of IL-17-family cytokines and other cytokines in splenic NK cells with intestinal CD3−NKp46+ cells that expressed different amounts of RORγt (Figure 3E). Curiously, intestinal NKp46+RORγt+ cells failed to express the signature cytokine IL-17A, although they expressed transcripts for the cytokines IL-17F and IL-22 (Figure 3E). Unlike splenic NK cells, intestinal NKp46+CD127+ subset cells also constitutively expressed transcripts for Csf2 (encoding granulocyte-macrophage colony-stimulating factor [GM-CSF]) and the chemokine Cxcl2 with amounts that positively correlated with RORγt expression (Figure 3E). Il22 expression could also be induced in intestinal LPL after activation in vitro (Figure 3F). Collectively, these results identify unique functional attributes of intestinal NKp46+ cell subsets that express RORγt and transcribe genes encoding GM-CSF, Cxcl2, and IL-22. We next sought to identify the signals that control the development and functional diversification of intestinal NKp46+ subsets. Because intestinal NKp46+ cells share some phenotypic similarities (CD127+, GATA-3+, and CD11blo) with thymus-derived NK cells (Vosshenrich et al., 2006Vosshenrich C.A. Garcia-Ojeda M.E. Samson-Villeger S.I. Pasqualetto V. Enault L. Richard-Le Goff O. Corcuff E. Guy-Grand D. Rocha B. Cumano A. et al.A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127.Nat. Immunol. 2006; 7: 1217-1224Crossref PubMed Scopus (357) Google Scholar), we determined whether they were related. We found normal numbers and distribution of intestinal CD3−NKp46+ cells in nude mice lacking the transcription factor Foxn1 (Figures 4A and 4B), suggesting that gut NKp46+ cell subsets are thymus independent. Intestinal CD3−NKp46+ cells also normally developed in the absence of antigen-receptor recombinase Rag2 (see below). IL-15 plays an essential role in the development, survival, and differentiation of NK1.1+ cells (Vosshenrich et al., 2005Vosshenrich C.A. Ranson T. Samson S.I. Corcuff E. Colucci F. Rosmaraki E.E. Di Santo J.P. Roles for common cytokine receptor gamma-chain-dependent cytokines in the generation, differentiation, and maturation of NK cell precursors and peripheral NK cells in vivo.J. Immunol. 2005; 174: 1213-1221PubMed Google Scholar). Analysis of Il15−/− mice confirmed a similar cytokine dependency of intestinal NKp46+NK1.1+ cells (Figures 4A and 4B). Interestingly, the absolute numbers of gut NKp46+CD127+NK1.1− cells were unaffected by the absence of IL-15, suggesting that the homeostasis of NKp46+ cells that differentially express NK1.1 may be controlled independently. Because RORγt plays an important role in the differentiation of Th17 lineage (Ivanov et al., 2006bIvanov I.I. McKenzie B.S. Zhou L. Tadokoro C.E. Lepelley A. Lafaille J.J. Cua D.J. Littman D.R. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.Cell. 2006; 126: 1121-1133Abstract Full Text Full Text PDF PubMed Scopus (3634) Google Scholar), we assessed whether RORγt was critical for the development and differentiation of gut NKp46+ cell subsets by using Rorc−/− mice (Eberl et al., 2004Eberl G. Marmon S. Sunshine M.J. Rennert P.D. Choi Y. Littman D.R. An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells.Nat. Immunol. 2004; 5: 64-73Crossref PubMed Scopus (738) Google Scholar). Strikingly, percentages and absolute numbers of intestinal NKp46+CD127+NK1.1− cells were strongly decreased in the absence of RORγt (Figures 4B and 4C). In contrast, homeostasis of intestinal NKp46+NK1.1+ cells appeared unaffected in Rorc−/− mice (Figures 4B and 4C). The intestine is in constant contact with commensal microorganisms, which impacts on the development of gut lymphoid st" @default.
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• W2155997615 date "2008-12-01" @default.
• W2155997615 modified "2023-10-16" @default.
• W2155997615 title "Microbial Flora Drives Interleukin 22 Production in Intestinal NKp46+ Cells that Provide Innate Mucosal Immune Defense" @default.
• W2155997615 cites W1542501019 @default.
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