RESUMO
Natural T helper 17 (nTH17) cells are a population of interleukin 17 (IL-17)-producing cells that acquire effector function in the thymus during development. Here we demonstrate that the serine/threonine kinase Akt has a critical role in regulating nTH17 cell development. Although Akt and the downstream mTORC1-ARNT-HIFα axis were required for generation of inducible TH17 (iTH17) cells, nTH17 cells developed independently of mTORC1. In contrast, mTORC2 and inhibition of Foxo proteins were critical for development of nTH17 cells. Moreover, distinct isoforms of Akt controlled the generation of TH17 cell subsets, as deletion of Akt2, but not of Akt1, led to defective generation of iTH17 cells. These findings define mechanisms regulating nTH17 cell development and reveal previously unknown roles of Akt and mTOR in shaping subsets of T cells.
Assuntos
Proteínas Proto-Oncogênicas c-akt/imunologia , Transdução de Sinais/imunologia , Serina-Treonina Quinases TOR/imunologia , Células Th17/imunologia , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Translocador Nuclear Receptor Aril Hidrocarboneto/imunologia , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Citometria de Fluxo , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Immunoblotting , Interleucina-17/imunologia , Interleucina-17/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Complexos Multiproteicos/imunologia , Complexos Multiproteicos/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Células Th17/metabolismoRESUMO
Interleukin (IL)-17 is a pro-inflammatory cytokine that plays critical roles in host defense against extracellular bacteria and fungi and also in the pathogenesis of autoimmune diseases. While CD4+ TCRαß+ T helper (Th) 17 cells are the best-described cellular source of IL-17, many innate-like T cells are in fact potent producers of IL-17. Given the increasing interest in therapeutic modulation of the IL-17 axis, it is crucial to better understand the cellular origins of IL-17 in various infection and diseases settings. While the diverse population of IL-17-producing T cells share many common characteristics, notable differences also exist. In this review, we discuss the heterogeneity of IL-17-producing T cell types focusing on their development, regulation, and function.
Assuntos
Células Th17/classificação , Animais , Autoimunidade , Citocinas/metabolismo , Humanos , Modelos Imunológicos , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Células Th17/citologia , Células Th17/fisiologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologiaRESUMO
CD4(+) Foxp3(+) regulatory T (Treg) cells are required for the maintenance of self-tolerance, as demonstrated by profound autoimmunity in mice and humans with inactivating Foxp3 mutations. Recent studies demonstrate that Treg cells are anatomically compartmentalized within secondary lymphoid organs based on their TCR repertoire and specific organ-protective function; however, whether this reflects differential homing or in situ selection is not known. Here, using Foxp3-GFP reporter mice, we have examined the ability of polyclonal Treg cells from cervical LNs to return to their site-of-origin following adoptive transfer to nonlymphopenic congenic recipients. We find that bulk cervical LN Treg cells do not home directly to cervical LNs but rather accumulate site specifically over time following transfer. Site-specific enrichment is both more rapid and more pronounced among a population of recently activated (CD69(+) ) Treg cells. These data suggest that compartmentalization of Treg cells within secondary lymphoid organs may be governed by antigen recognition and implicate CD69 as a potential marker of recently activated Treg cells recognizing locally expressed antigens.
Assuntos
Transferência Adotiva , Fatores de Transcrição Forkhead/análise , Linfócitos T Reguladores/fisiologia , Animais , Antígenos CD/fisiologia , Antígenos de Diferenciação de Linfócitos T/fisiologia , Compartimento Celular , Movimento Celular , Lectinas Tipo C/fisiologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/imunologiaRESUMO
CD4(+) T helper 17 (Th17) cells play a critical role in the adaptive immune response against extracellular pathogens. Most studies to date have focused on understanding the differentiation of Th17 cells from naive CD4(+) T cells in peripheral effector sites. However, Th17 cells are present in the thymus. In this study, we demonstrate that a population of Th17 cells, natural Th17 cells (nTh17 cells), which acquire effector function during development in the thymus before peripheral antigen exposure, shows preferential usage of T cell receptor Vß3. nTh17 cells are dependent on major histocompatibility complex (MHC) class II for thymic selection, yet unlike conventional CD4(+) T cells, MHC class II expression on thymic cortical epithelium is not sufficient for their development, rather expression on medullary epithelium is necessary. Differential signaling requirements for IL-17 priming further distinguish nTh17 from conventional Th17 cells. Collectively, our findings define a Th17 population, poised to rapidly produce cytokines, that is developmentally distinct from conventional Th17 cells and that potentially functions at the interface of innate and adaptive immunity.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/fisiologia , Interleucina-17/imunologia , Células Th17/imunologia , Células Th17/fisiologia , Imunidade Adaptativa/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Diferenciação Celular/imunologia , Células Cultivadas , Citocinas/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Imunidade Inata/imunologia , Complexo Principal de Histocompatibilidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Quimera por Radiação , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Células Th17/citologia , Timo/citologia , Timo/imunologiaRESUMO
Polarized segregation of proteins in T cells is thought to play a role in diverse cellular functions including signal transduction, migration, and directed secretion of cytokines. Persistence of this polarization can result in asymmetric segregation of fate-determining proteins during cell division, which may enable a T cell to generate diverse progeny. Here, we provide evidence that a lineage-determining transcription factor, T-bet, underwent asymmetric organization in activated T cells preparing to divide and that it was unequally partitioned into the two daughter cells. This unequal acquisition of T-bet appeared to result from its asymmetric destruction during mitosis by virtue of concomitant asymmetric segregation of the proteasome. These results suggest a mechanism by which a cell may unequally localize cellular activities during division, thereby imparting disparity in the abundance of cell fate regulators in the daughter cells.
Assuntos
Mitose , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas com Domínio T/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Animais , Polaridade Celular , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Proteínas com Domínio T/metabolismo , Linfócitos T/enzimologiaRESUMO
Conventional and nonconventional T cell development occur in the thymus. Nonconventional thymocytes that bear characteristics typically associated with innate immune cells are termed innate-like lymphocytes (ILLs). Mice harboring a tyrosine to phenylalanine mutation in the adaptor protein Src homology 2 domain-containing leukocyte protein of 76 kDa at residue 145 (Y145F mice) develop an expanded population of CD8(+)CD122(+)CD44(+) ILLs, typified by expression of the T-box transcription factor eomesodermin. Y145F mice also have an expanded population of γδ T cells that produce copious amounts of IL-4 via a mechanism that is dependent on the BTB-ZF transcription factor promyelocytic leukemia zinc finger. Using mice with T cell-specific deletion of Eomes, we demonstrate that this transcription factor is required for CD8(+) ILL development in Y145F as well as wild-type mice. Moreover, we show that promyelocytic leukemia zinc finger and IL-4 are also required for the generation of this ILL population. Taken together, these data shed light on the cell-intrinsic and cell-extrinsic factors that drive CD8(+) ILL differentiation.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Linfócitos T CD8-Positivos/imunologia , Fatores de Transcrição Kruppel-Like/imunologia , Fosfoproteínas/imunologia , Proteínas com Domínio T/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Substituição de Aminoácidos , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Citometria de Fluxo , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-4/imunologia , Interleucina-4/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Fosfoproteínas/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica , Proteínas com Domínio T/genética , Timo/citologia , Timo/imunologia , Timo/metabolismo , Dedos de Zinco/genética , Dedos de Zinco/imunologiaRESUMO
SH2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) nucleates a signaling complex critical for T-cell receptor (TCR) signal propagation. Mutations in the tyrosines of SLP-76 result in graded defects in TCR-induced signals depending on the tyrosine(s) affected. Here we use 2 strains of genomic knock-in mice expressing tyrosine to phenylalanine mutations to examine the role of TCR signals in the differentiation of effector and memory CD8(+) T cells in response to infection in vivo. Our data support a model in which altered TCR signals can determine the rate of memory versus effector cell differentiation independent of initial T-cell expansion. Furthermore, we show that TCR signals sufficient to promote CD8(+) T-cell differentiation are different from those required to elicit inflammatory cytokine production.