RESUMO
Whether the recently identified innate lymphocyte population coexpressing natural killer cell receptors (NKRs) and the nuclear receptor RORγt is part of the NK or lymphoid tissue inducer (LTi) cell lineage remains unclear. By using adoptive transfer of genetically tagged LTi-like cells, we demonstrate that NKRâ»RORγt(+) innate lymphocytes but not NK cells were direct progenitors to NKR(+)RORγt(+) cells in vivo. Genetic lineage tracing revealed that the differentiation of LTi-like cells was characterized by the stable upregulation of NKRs and a progressive loss of RORγt expression. Whereas interleukin-7 (IL-7) and intestinal microbiota stabilized RORγt expression within such NKR-LTi cells, IL-12 and IL-15 accelerated RORγt loss. RORγt(+) NKR-LTi cells produced IL-22, whereas RORγtâ» NKR-LTi cells released IFN-γ and were potent inducers of colitis. Thus, the RORγt gradient in NKR-LTi cells serves as a tunable rheostat for their functional program. Our data also define a previously unappreciated role of RORγtâ» NKR-LTi cells for the onset or maintenance of inflammatory bowel diseases.
Assuntos
Células Matadoras Naturais/imunologia , Tecido Linfoide/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Animais , Linhagem da Célula/imunologia , Regulação para Baixo , Doenças Inflamatórias Intestinais/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-12/imunologia , Interleucina-12/metabolismo , Interleucina-15/imunologia , Interleucina-15/metabolismo , Interleucina-7/genética , Interleucina-7/imunologia , Interleucina-7/metabolismo , Interleucinas/imunologia , Interleucinas/metabolismo , Intestinos/imunologia , Intestinos/microbiologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Regulação para Cima , Interleucina 22RESUMO
Recently, additional innate lymphocyte subsets have been identified that express germline encoded immunoreceptors and respond to cytokine cues. Among these, innate lymphoid cells (ILC) at mucosal surfaces are of significant interest because they were found to play important roles for lymphoid organogenesis, tissue homeostasis and repair, for immunity to various infections but also have been involved as disease-promoting cells in models of chronic inflammatory diseases and of autoimmunity. Their functional and transcriptional programs strikingly resemble that of the various T helper cell subsets suggesting that these programs are already pre-formed in the innate immune system and that these may be more conserved than previously appreciated. Interestingly, all ILC subsets express the interleukin 7 receptor α chain and IL-7 signaling has been involved in various aspects of their developmental and functional programs. Here, we will review the role of IL-7 signaling for the differentiation, maintenance and function of two important ILC subsets, lymphoid tissue inducer cells (i.e., RORγt(+) ILC) and natural helper cells (i.e., type 2 ILC). We will also put emphasis on the recently discovered role of IL-7 in controlling plasticity of RORγt(+) ILC.
Assuntos
Imunidade Inata , Interleucina-7/imunologia , Linfócitos/imunologia , Transdução de Sinais , Animais , Diferenciação Celular , Linhagem da Célula , Humanos , Interleucina-7/metabolismo , Linfócitos/citologia , Linfócitos/metabolismoRESUMO
It is rapidly emerging that the defence system of innate lymphocytes is more diverse than previously recognized. In addition to natural killer (NK) cells, lymphoid tissue inducer (LTi) cells, and natural helper cells have now been identified. LTi cells are developmentally dependent on the orphan transcription factor RORγt and instruct lymph node development during embryogenesis. More recently, it has become evident, that in addition to their role for lymph organ development, LTi cells are also potent producers of cytokines such as interleukin-22 (IL-22) and IL-17 in adult mice. In addition to LTi cells, another RORγt-dependent innate lymphocyte subset co-expressing RORγt and NK cell receptors (NKRs) has been identified. These NKR(+) RORγt(+) cells are also potent producers of IL-22 but it is unclear whether they are part of the NK cell or LTi cell lineage. This review will highlight recent progress in understanding development and function of innate IL-22-producing lymphocyte subsets.
Assuntos
Células Epiteliais/imunologia , Interleucinas/imunologia , Linfócitos/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Animais , Linhagem da Célula/imunologia , Células Epiteliais/metabolismo , Humanos , Interleucinas/metabolismo , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Linfócitos/metabolismo , Camundongos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Receptores de Células Matadoras Naturais/imunologia , Receptores de Células Matadoras Naturais/metabolismo , Interleucina 22RESUMO
BACKGROUND: Impaired Fas-induced apoptosis of lymphocytes in vitro is a principal feature of the autoimmune lymphoproliferative syndrome (ALPS). We studied six children with ALPS whose lymphocytes had normal sensitivity to Fas-induced apoptosis in vitro. METHODS: Susceptibility to Fas-mediated apoptosis and the Fas gene were analyzed in purified subgroups of T cells and other mononuclear cells from six patients with ALPS type III. RESULTS: Heterozygous dominant Fas mutations were detected in the polyclonal double-negative T cells from all six patients. In two patients, these mutations were found in a fraction of CD4+ and CD8+ T cells, monocytes, and CD34+ hematopoietic precursors, but not in hair or mucosal epithelial cells. CONCLUSIONS: Somatic heterozygous mutations of Fas can cause a sporadic form of ALPS by allowing lymphoid precursors to resist the normal process of cell death.
Assuntos
Doenças Autoimunes/genética , Transtornos Linfoproliferativos/genética , Mutação , Receptor fas/genética , Adolescente , Apoptose , Doenças Autoimunes/classificação , Células Cultivadas , Criança , Análise Mutacional de DNA , Feminino , Expressão Gênica , Hematopoese/genética , Hematopoese/fisiologia , Heterozigoto , Humanos , Transtornos Linfoproliferativos/classificação , Masculino , Mosaicismo , Fenótipo , Reação em Cadeia da Polimerase , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos TAssuntos
Dieta , Imunidade , Receptores de Hidrocarboneto Arílico/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Alimentos , Regulação da Expressão Gênica , Substâncias Perigosas/farmacocinética , Homeostase , Humanos , Intestinos/imunologia , Intestinos/microbiologia , Células Matadoras Naturais/imunologia , Tecido Linfoide/imunologia , Camundongos , Camundongos Knockout , Modelos Biológicos , Modelos Imunológicos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Tolerância a Antígenos Próprios , Xenobióticos/farmacocinéticaAssuntos
Imunidade Inata/fisiologia , Doenças Inflamatórias Intestinais/imunologia , Interleucina-23/imunologia , Mucosa Intestinal/imunologia , Animais , Doença de Crohn/imunologia , Modelos Animais de Doenças , Humanos , Doenças Inflamatórias Intestinais/patologia , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , CamundongosRESUMO
Intestinal homeostasis results from a complex mutualism between gut microbiota and host cells. Defining the molecular network regulating such mutualism is currently of increasing interest, as its deregulation is reported to lead to increased susceptibility to infections, chronic inflammatory bowel diseases and cancer. Until now, the focus has been on the mechanism, by which the composition of indigenous microbiota shapes the immune system. In a recent study, we have shown that dietary compounds have also the ability to affect innate immune system. This regulation involves aryl hydrocarbon receptor (AhR), a sensor of plant-derived phytochemicals, which mediates the maintenance of Retinoic acid related orphan receptor γ t-expressing innate lymphoid cells (RORγt(+) ILC) in the gut and consequently formation of postnatal lymphoid follicles. Thus, AhR represents the first evidence of a molecular link between diet and immunity at intestinal mucosal surfaces.
Assuntos
Dieta , Mucosa Intestinal/imunologia , Tecido Linfoide/fisiologia , Receptores de Hidrocarboneto Arílico/fisiologia , Animais , Humanos , Mucosa Intestinal/efeitos dos fármacos , Linfócitos/fisiologia , Tecido Linfoide/efeitos dos fármacos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/biossínteseRESUMO
Innate lymphoid cells (ILC) expressing the transcription factor RORγt induce the postnatal formation of intestinal lymphoid follicles and regulate intestinal homeostasis. RORγt(+) ILC express the aryl hydrocarbon receptor (AhR), a highly conserved, ligand-inducible transcription factor believed to control adaptation of multicellular organisms to environmental challenges. We show that AhR is required for the postnatal expansion of intestinal RORγt(+) ILC and the formation of intestinal lymphoid follicles. AhR activity within RORγt(+) ILC could be induced by dietary ligands such as those contained in vegetables of the family Brassicaceae. AhR-deficient mice were highly susceptible to infection with Citrobacter rodentium, a mouse model for attaching and effacing infections. Our results establish a molecular link between nutrients and the formation of immune system components required to maintain intestinal homeostasis and resistance to infections.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Intestino Delgado/citologia , Linfócitos/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem Celular Tumoral , Citrobacter rodentium/imunologia , Dieta , Infecções por Enterobacteriaceae/imunologia , Intestino Delgado/imunologia , Ligantes , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Organogênese , Receptores de Hidrocarboneto Arílico/deficiência , Receptores de Hidrocarboneto Arílico/genéticaRESUMO
Although NK cells were originally identified as "naturally" active cells believed to follow a cell-autonomous activation program, it is now widely accepted that NK cells need to interact with dendritic cells for their full functional activation and for their homeostasis. In this chapter, we will provide an experimental guide to the analysis of NK cell/DC interactions in vitro and in vivo. We have put special emphasis on the recently developed mouse models allowing the inducible and specific ablation of various subsets of DCs and other myeloid cells.
Assuntos
Comunicação Celular , Células Dendríticas/citologia , Células Matadoras Naturais/citologia , Animais , Biomarcadores/metabolismo , Células da Medula Óssea/citologia , Linhagem Celular , Citocinas/metabolismo , Células Dendríticas/metabolismo , Engenharia Genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Espaço Intracelular/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Macrófagos/citologia , Camundongos , Modelos Biológicos , Células Mieloides/metabolismo , Coloração e Rotulagem , Receptores Toll-Like/metabolismoRESUMO
Fas-induced apoptosis, a key event in the regulation of lymphocyte homeostasis, is mainly mediated by the activation of a cascade of caspases. Using caspase- and Fas-associated death domain protein-deficient Jurkat cell lines as well as a pan-caspase inhibitor (Z-VAD-fmk), we observed a second Fas-induced cell death event, independent of any known caspase activation. This pathway is of slow kinetics and displays some features of necrosis. However, this caspase-independent pathway does not seem to play a significant role in the Fas-mediated death of primary activated T cell blasts. Indeed, in this setting, Fas-induced cell death was always substantially inhibited by Z-VAD-fmk, suggesting that caspase activation is an absolute requirement in the Fas-induced death of primary human T lymphocytes.