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1.
Nat Immunol ; 21(11): 1467, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32884131

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

2.
Nature ; 567(7749): 525-529, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30814730

RESUMO

T cells become dysfunctional when they encounter self antigens or are exposed to chronic infection or to the tumour microenvironment1. The function of T cells is tightly regulated by a combinational co-stimulatory signal, and dominance of negative co-stimulation results in T cell dysfunction2. However, the molecular mechanisms that underlie this dysfunction remain unclear. Here, using an in vitro T cell tolerance induction system in mice, we characterize genome-wide epigenetic and gene expression features in tolerant T cells, and show that they are distinct from effector and regulatory T cells. Notably, the transcription factor NR4A1 is stably expressed at high levels in tolerant T cells. Overexpression of NR4A1 inhibits effector T cell differentiation, whereas deletion of NR4A1 overcomes T cell tolerance and exaggerates effector function, as well as enhancing immunity against tumour and chronic virus. Mechanistically, NR4A1 is preferentially recruited to binding sites of the transcription factor AP-1, where it represses effector-gene expression by inhibiting AP-1 function. NR4A1 binding also promotes acetylation of histone 3 at lysine 27 (H3K27ac), leading to activation of tolerance-related genes. This study thus identifies NR4A1 as a key general regulator in the induction of T cell dysfunction, and a potential target for tumour immunotherapy.


Assuntos
Regulação da Expressão Gênica/genética , Genoma , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Linfócitos T/metabolismo , Linfócitos T/patologia , Acetilação , Animais , Infecções por Arenaviridae/imunologia , Infecções por Arenaviridae/virologia , Linhagem Celular Tumoral , Colite/imunologia , Colite/patologia , Colite/terapia , Epigênese Genética , Feminino , Histonas/química , Histonas/metabolismo , Tolerância Imunológica/genética , Imunoterapia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Linfócitos T/imunologia , Fator de Transcrição AP-1/metabolismo , Transcrição Gênica
3.
Nat Immunol ; 10(12): 1260-6, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19881507

RESUMO

How naive CD4(+) T cells commit to the T helper type 2 (T(H)2) lineage is poorly understood. Here we show that the basic helix-loop-helix transcription factor Dec2 was selectively expressed in T(H)2 cells. CD4(+) T cells from Dec2-deficient mice showed defective T(H)2 differentiation in vitro and in vivo in an asthma model and in response to challenge with a parasite antigen. Dec2 promoted expression of interleukin 4 (IL-4), IL-5 and IL-13 during early T(H)2 differentiation and directly bound to and activated transcription of genes encoding the transcription factors JunB and GATA-3. As GATA-3 induces Dec2 expression, our findings also indicate a feed-forward regulatory circuit during T(H)2 differentiation.


Assuntos
Linhagem da Célula , Células Th2/citologia , Células Th2/imunologia , Fatores de Transcrição/imunologia , Animais , Asma/imunologia , Asma/metabolismo , Diferenciação Celular , Modelos Animais de Doenças , Fator de Transcrição GATA3/metabolismo , Camundongos , Camundongos Knockout , Ligação Proteica , Proteínas Proto-Oncogênicas c-jun/metabolismo , Células Th2/metabolismo , Fatores de Transcrição/deficiência , Fatores de Transcrição/metabolismo
4.
Immunity ; 36(1): 23-31, 2012 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-22244845

RESUMO

T helper 17 (Th17) cells specifically transcribe the Il17 and Il17f genes, which are localized in the same chromosome region, but the underlying mechanism is unclear. Here, we report a cis element that we previously named conserved noncoding sequence 2 (CNS2) physically interacted with both Il17 and Il17f gene promoters and was sufficient for regulating their selective transcription in Th17 cells. Targeted deletion of CNS2 resulted in impaired retinoic acid-related orphan receptor gammat (RORγt)-driven IL-17 expression in vitro. CNS2-deficient T cells also produced substantially decreased amounts of IL-17F. These cytokine defects were associated with defective chromatin remodeling in the Il17-Il17f gene locus, possibly because of effects on CNS2-mediated recruitment of histone-modifying enzymes p300 and JmjC domain-containing protein 3 (JMJD3). CNS2-deficient animals were also shown to be resistant to experimental autoimmune encephalomyelitis (EAE). Our results thus suggest that CNS2 is sufficient and necessary for Il17 and optimal Il17f gene transcription in Th17 cells.


Assuntos
Sequência Conservada , Regulação da Expressão Gênica , Interleucina-17/genética , Regiões Promotoras Genéticas , Pequeno RNA não Traduzido , Animais , Encefalomielite Autoimune Experimental/genética , Interleucina-17/metabolismo , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Elementos Reguladores de Transcrição
5.
Nature ; 507(7493): 513-8, 2014 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-24463518

RESUMO

In immune responses, activated T cells migrate to B-cell follicles and develop into follicular T-helper (TFH) cells, a recently identified subset of CD4(+) T cells specialized in providing help to B lymphocytes in the induction of germinal centres. Although Bcl6 has been shown to be essential in TFH-cell function, it may not regulate the initial migration of T cells or the induction of the TFH program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation. Here we show that expression of achaete-scute homologue 2 (Ascl2)--a basic helix-loop-helix (bHLH) transcription factor--is selectively upregulated in TFH cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6, and downregulates C-C chemokine receptor 7 (CCR7) expression in T cells in vitro, as well as accelerating T-cell migration to the follicles and TFH-cell development in vivo in mice. Genome-wide analysis indicates that Ascl2 directly regulates TFH-related genes whereas it inhibits expression of T-helper cell 1 (TH1) and TH17 signature genes. Acute deletion of Ascl2, as well as blockade of its function with the Id3 protein in CD4(+) T cells, results in impaired TFH-cell development and germinal centre response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances TFH-cell generation. Thus, Ascl2 directly initiates TFH-cell development.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular , Centro Germinativo/citologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular/genética , Movimento Celular , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo , Centro Germinativo/imunologia , Humanos , Proteínas Inibidoras de Diferenciação/genética , Proteínas Inibidoras de Diferenciação/metabolismo , Camundongos , Mutação/genética , Proteínas Proto-Oncogênicas c-bcl-6 , Receptores CCR7/metabolismo , Receptores CXCR5/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Células Th17/citologia , Células Th17/imunologia , Células Th17/metabolismo , Transcrição Gênica/genética , Regulação para Cima
6.
Immunity ; 32(5): 692-702, 2010 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-20434372

RESUMO

Toll-like receptors (TLRs) have previously been shown to play critical roles in the activation of innate immunity. Here, we describe that T cell expression of TLR2 regulates T helper 17 (Th17) cell responses. Stimulation with TLR2 agonists promoted Th17 differentiation in vitro and led to more robust proliferation and Th17 cytokine production. Using the experimental autoimmune encephalomyelitis (EAE) model, we found that TLR2 regulated Th17 cell-mediated autoimmunity in vivo and that loss of TLR2 in CD4(+) T cells dramatically ameliorated EAE. This study thus reveals a critical role of a TLR in the direct regulation of adaptive immune response and pathogenesis of autoimmune diseases.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Encefalomielite Autoimune Experimental/fisiopatologia , Interleucina-17/metabolismo , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/imunologia , Receptor 2 Toll-Like/fisiologia , Animais , Linfócitos T CD4-Positivos/citologia , Diferenciação Celular , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Deleção de Genes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Auxiliares-Indutores/citologia , Receptor 2 Toll-Like/genética
7.
Immunity ; 32(5): 670-80, 2010 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-20493730

RESUMO

T cell activation is tightly regulated to avoid autoimmunity. Gene related to anergy in lymphocytes (GRAIL, encoded by Rnf128) is an E3 ubiquitin ligase associated with T cell tolerance. Here, we generated and analyzed GRAIL-deficient mice and found they were resistant to immune tolerance induction and exhibited greater susceptibility to autoimmune diseases than wild-type mice. GRAIL-deficient naive T cells, after activation, exhibited increased proliferation and cytokine expression than controls and did not depend on costimulation for effector generation. Moreover, GRAIL-deficient regulatory T (Treg) cells displayed reduced suppressive function, associated with increased Th17 cell-related gene expression. GRAIL-deficient naive and Treg cells were less efficient in downregulating T cell receptor (TCR)-CD3 expression after activation and exhibited increased NFATc1 transcription factor expression; GRAIL expression promoted CD3 ubiquitinylation. Our results indicate that GRAIL, by mediating TCR-CD3 degradation, regulates naive T cell tolerance induction and Treg cell function.


Assuntos
Complexo CD3/imunologia , Tolerância Imunológica/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Ubiquitina-Proteína Ligases/imunologia , Animais , Regulação da Expressão Gênica , Immunoblotting , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Linfócitos T Reguladores/enzimologia , Ubiquitina-Proteína Ligases/genética
8.
J Immunol ; 199(8): 2815-2822, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28855309

RESUMO

In this study, we determined the role of IL-21R signaling in Mycobacterium tuberculosis infection, using IL-21R knockout (KO) mice. A total of 50% of M. tuberculosis H37Rv-infected IL-21R KO mice died in 6 mo compared with no deaths in infected wild type (WT) mice. M. tuberculosis-infected IL-21R KO mice had enhanced bacterial burden and reduced infiltration of Ag-specific T cells in lungs compared with M. tuberculosis-infected WT mice. Ag-specific T cells from the lungs of M. tuberculosis-infected IL-21R KO mice had increased expression of T cell inhibitory receptors, reduced expression of chemokine receptors, proliferated less, and produced less IFN- γ, compared with Ag-specific T cells from the lungs of M. tuberculosis-infected WT mice. T cells from M. tuberculosis-infected IL-21R KO mice were unable to induce optimal macrophage responses to M. tuberculosis. This may be due to a decrease in the Ag-specific T cell population. We also found that IL-21R signaling is associated with reduced expression of a transcriptional factor Eomesodermin and enhanced functional capacity of Ag-specific T cells of M. tuberculosis-infected mice. The sum of our findings suggests that IL-21R signaling is essential for the optimal control of M. tuberculosis infection.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Pulmão/imunologia , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Receptores de Interleucina-21/metabolismo , Tuberculose/imunologia , Animais , Proliferação de Células , Células Cultivadas , Feminino , Humanos , Interferon gama/metabolismo , Pulmão/microbiologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-21/genética , Transdução de Sinais , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo
9.
J Immunol ; 199(10): 3453-3465, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-29055004

RESUMO

The metabolic syndrome and diabetic conditions support atherosclerosis, but the exact mechanisms for accelerated atherogenesis remain unclear. Although the proinflammatory role of STAT4 in atherosclerosis and diet-induced insulin resistance (IR) was recently established, the impact of STAT4 on atherogenesis in conditions of IR is not known. In this study, we generated Stat4-/-Ldlr-/- mice that were fed a diabetogenic diet with added cholesterol (DDC). DDC-fed Stat4-/-Ldlr-/- mice demonstrated improved glucose tolerance, insulin sensitivity, and a 36% reduction in atherosclerosis compared with Ldlr-/- controls. Interestingly, we detected a reduction in T follicular helper (Tfh) cells and plasma B cells but a sharp elevation in CD8+ regulatory T cells (Tregs) in spleens and aortas of Stat4-/-Ldlr-/- mice compared with Ldlr-/- mice. Similarly, STAT4 deficiency supported CD8+ Treg differentiation in vitro. STAT4-deficient CD8+ Tregs suppressed Tfh cell and germinal center B cell development upon immunization with keyhole limpet hemocyanin, indicating an important role for STAT4 in CD8+ Treg functions in vivo. Furthermore, adoptive transfer of Stat4-/-Ldlr-/- CD8+ Tregs versus Ldlr-/- CD8+ Tregs resulted in a significant reduction in plaque burden and suppression of Tfh cell and germinal center B cells in DDC-fed Ldlr-/- recipients. STAT4 expression in macrophages (MΦs) also affected the Tfh/CD8+ Treg axis, because conditioned media from Stat4-/-Ldlr-/- MΦs supported CD8+ Treg differentiation, but not Tfh cell differentiation, in a TGF-ß-dependent manner. These findings suggest a novel mechanism by which STAT4 supports atherosclerosis in IR Ldlr-/- mice via STAT4-dependent MΦs, as well as cell-intrinsic suppression of CD8+ Treg generation and functions and maintenance of Tfh cell generation and the accompanying humoral immune response.


Assuntos
Aterosclerose/imunologia , Receptores de LDL/metabolismo , Fator de Transcrição STAT4/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos CD8/metabolismo , Células Cultivadas , Colesterol/metabolismo , Dieta Aterogênica , Centro Germinativo/imunologia , Humanos , Resistência à Insulina , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de LDL/genética , Fator de Transcrição STAT4/genética
10.
J Allergy Clin Immunol ; 141(6): 2061-2073.e5, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28943467

RESUMO

BACKGROUND: Allergic asthma is a heterogeneous chronic inflammatory disease of the airways with a massive infiltration of eosinophils or neutrophils mediated by allergen-specific TH2 and TH17 cells, respectively. Therefore successful treatment of allergic asthma will require suppression of both TH2 and TH17 cells. OBJECTIVE: We sought to investigate the role of the TH17 cell pathway in regulating TH2 cell responses in allergic asthma. METHODS: Allergic asthma was induced by intranasal challenge with proteinase allergens in C57BL/6, Il17a-/-Il17f-/-, and retinoic acid receptor-related orphan receptor γt (RORγt)gfp/gfp mice. A pharmacologic RORγt inhibitor was used to evaluate its preventive and therapeutic effects in allergic asthma. Characteristics of allergic airway inflammation were analyzed by using flow cytometry, histology, quantitative real-time PCR, and ELISA. Mixed bone marrow chimeric mice, fate mapping analysis, short hairpin RNA transduction, and in vitro T-cell differentiation were used for mechanistic studies. RESULTS: Mice deficient in IL-17A and IL-17F, as well as RORγt, exhibited a significant reduction not only in TH17 cell responses but also in TH2 cell responses in an animal model of allergic asthma. Similarly, mice treated with an RORγt inhibitor had significantly diminished TH17 and TH2 cell responses, leading to reduced neutrophil and eosinophil numbers in the airway. RORγt-deficient T cells were intrinsically defective in differentiating into TH2 cells and expressed increased levels of B-cell lymphoma 6 (Bcl6). Bcl6 knockdown resulted in a remarkable restoration of TH2 cell differentiation in RORγt-deficient T cells. Blockade of RORγt also significantly hampered the differentiation of human TH2 and TH17 cells from naive CD4+ T cells. CONCLUSION: RORγt in T cells is required for optimal TH2 cell differentiation by suppressing Bcl6 expression; this finding suggests that targeting RORγt might be a promising approach for the treatment of allergic asthma by concomitantly suppressing TH17 and TH2 cell responses in the airway.


Assuntos
Asma/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Células Th17/imunologia , Células Th2/imunologia , Animais , Diferenciação Celular/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores
11.
Immunity ; 30(4): 576-87, 2009 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-19362022

RESUMO

T helper (Th) 17 cells have been recently discovered in both mouse and human. Here we show that interleukin-1 (IL-1) signaling on T cells is critically required for the early programming of Th17 cell lineage and Th17 cell-mediated autoimmunity. IL-1 receptor1 expression in T cells, which was induced by IL-6, was necessary for the induction of experimental autoimmune encephalomyelitis and for early Th17 cell differentiation in vivo. Moreover, IL-1 signaling in T cells was required in dendritic cell-mediated Th17 cell differentiation from naive or regulatory precursors and IL-1 synergized with IL-6 and IL-23 to regulate Th17 cell differentiation and maintain cytokine expression in effector Th17 cells. Importantly, IL-1 regulated the expression of the transcription factors IRF4 and RORgammat during Th17 cell differentiation; overexpression of these two factors resulted in IL-1-independent Th17 cell polarization. Our data thus indicate a critical role of IL-1 in Th17 cell differentiation and this pathway may serve as a unique target for Th17 cell-mediated immunopathology.


Assuntos
Diferenciação Celular , Regulação da Expressão Gênica , Interleucina-1/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/citologia , Linfócitos T Auxiliares-Indutores/citologia , Animais , Linhagem da Célula , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/biossíntese , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Regulação para Cima
12.
Immunity ; 29(6): 841-3, 2008 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-19100696
13.
Immunity ; 29(1): 138-49, 2008 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-18599325

RESUMO

After activation, CD4(+) helper T (Th) cells differentiate into distinct effector subsets. Although chemokine (C-X-C motif) receptor 5-expressing T follicular helper (Tfh) cells are important in humoral immunity, their developmental regulation is unclear. Here we show that Tfh cells had a distinct gene expression profile and developed in vivo independently of the Th1 or Th2 cell lineages. Tfh cell generation was regulated by ICOS ligand (ICOSL) expressed on B cells and was dependent on interleukin-21 (IL-21), IL-6, and signal transducer and activator of transcription 3 (STAT3). However, unlike Th17 cells, differentiation of Tfh cells did not require transforming growth factor beta (TGF-beta) or Th17-specific orphan nuclear receptors RORalpha and RORgamma in vivo. Finally, naive T cells activated in vitro in the presence of IL-21 but not TGF-beta signaling preferentially acquired Tfh gene expression and promoted germinal-center reactions in vivo. This study thus demonstrates that Tfh is a distinct Th cell lineage.


Assuntos
Diferenciação Celular/imunologia , Linhagem da Célula/imunologia , Centro Germinativo/citologia , Interleucinas/imunologia , Subpopulações de Linfócitos T/citologia , Linfócitos T Auxiliares-Indutores/citologia , Transferência Adotiva , Animais , Linfócitos B/imunologia , Citometria de Fluxo , Expressão Gênica , Perfilação da Expressão Gênica , Centro Germinativo/imunologia , Imuno-Histoquímica , Ligante Coestimulador de Linfócitos T Induzíveis , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-6/imunologia , Interleucina-6/metabolismo , Interleucinas/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Mutantes , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas/imunologia , Proteínas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo
14.
Immunity ; 29(1): 44-56, 2008 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-18585065

RESUMO

Regulatory T (Treg) and T helper 17 (Th17) cells were recently proposed to be reciprocally regulated during differentiation. To understand the underlying mechanisms, we utilized a Th17 reporter mouse with a red fluorescent protein (RFP) sequence inserted into the interleukin-17F (IL-17F) gene. Using IL-17F-RFP together with a Foxp3 reporter, we found that the development of Th17 and Foxp3(+) Treg cells was associated in immune responses. Although TGF-beta receptor I signaling was required for both Foxp3 and IL-17 induction, SMAD4 was only involved in Foxp3 upregulation. Foxp3 inhibited Th17 differentiation by antagonizing the function of the transcription factors RORgammat and ROR*. In contrast, IL-6 overcame this suppressive effect of Foxp3 and, together with IL-1, induced genetic reprogramming in Foxp3(+) Treg cells. STAT3 regulated Foxp3 downregulation, whereas STAT3, RORgamma, and ROR* were required for IL-17 expression in Treg cells. Our data demonstrate molecular antagonism and plasticity of Treg and Th17 cell programs.


Assuntos
Diferenciação Celular/imunologia , Inflamação/imunologia , Subpopulações de Linfócitos T/citologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Reguladores/citologia , Animais , Encefalomielite Autoimune Experimental/imunologia , Feminino , Citometria de Fluxo , Imunoprecipitação , Interleucina-17/imunologia , Interleucina-17/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Transgênicos , Reação em Cadeia da Polimerase , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Transdução Genética , Fator de Crescimento Transformador beta1/imunologia , Fator de Crescimento Transformador beta1/metabolismo
16.
Immunol Rev ; 252(1): 139-45, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23405901

RESUMO

T-follicular helper (Tfh) cells are a new subset of effector CD4(+) T cells that are specialized in helping B cells in the germinal center reaction. Tfh cells are distinct from other established CD4(+) T-cell lineages, Th1, Th2, Th17, and T-regulatory cells, in their gene expression profiles. Tfh cell differentiation results from a network of transcriptional regulation by a master transcriptional factor Bcl6 as well as IRF4, c-Maf, Batf, and STAT3/5. During Tfh cell ontogeny, increased CXCR5 expression directs activated T-cell migration to the follicles, and their interaction with B cells leads to Bcl6 upregulation, which helps establish effector and memory Tfh cell program. This review summarizes the recent progress in molecular mechanisms underlying Tfh differentiation and discusses the future perspectives for this important area of research.


Assuntos
Linfócitos B/imunologia , Proteínas de Ligação a DNA/imunologia , Centro Germinativo/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Transcrição Gênica , Linfócitos B/citologia , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Linhagem da Célula/imunologia , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Centro Germinativo/citologia , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Proteínas Proto-Oncogênicas c-bcl-6 , Proteínas Proto-Oncogênicas c-maf/genética , Proteínas Proto-Oncogênicas c-maf/imunologia , Receptores CXCR5/genética , Receptores CXCR5/imunologia , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/imunologia , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/citologia
17.
Cytokine ; 87: 9-19, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27339151

RESUMO

T follicular helper (Tfh) cells are specialized subset of T helper (Th) cells necessary for germinal center reaction, affinity maturation and the differentiation of germinal center B cells to antibody-producing plasma B cells and memory B cells. The differentiation of Tfh cells is a multistage, multifactorial process involving a variety of cytokines, surface molecules and transcription factors. While Tfh cells are critical components of protective immune responses against pathogens, regulation of these cells is crucial to prevent autoimmunity and airway inflammation. Recently, it has been noted that Tfh cells could be potentially implicated either in cancer progression or prevention. Thus, the elucidation of the mechanisms that regulate Tfh cell differentiation, function and fate should highlight potential targets for novel therapeutic approaches. In this review, we summarize the latest advances in our understanding of the regulation of Tfh cell differentiation and their role in health and disease.


Assuntos
Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/fisiologia , Animais , Autoimunidade , Linfócitos B/imunologia , Diferenciação Celular , Citocinas/imunologia , Regulação da Expressão Gênica , Centro Germinativo/citologia , Humanos , Memória Imunológica , Interleucina-4/biossíntese , Interleucina-4/imunologia , Ativação Linfocitária , Camundongos , Células Th2/imunologia
18.
J Immunol ; 193(12): 6152-60, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25398328

RESUMO

Humoral immunity, including Ab switching and somatic hypermutation, is critically regulated by CD4(+) T cells. T follicular helper (Tfh) cells have been recently shown to be a distinct T cell subset important in germinal center reactions. The transcriptional regulation of Tfh cell development and function has not been well understood. In this study, we report that C/EBPα, a basic region/leucine zipper transcription factor, is highly expressed in Tfh cells. Cebpa-deficient CD4(+) T cells exhibit enhanced IFN-γ expression in vitro and in vivo. T cell-specific Cebpa knockout mice, although not defective in Tfh cell generation, produce significantly increased levels of IgG2a/b and IgG3 following immunization with a protein Ag. Moreover, C/EBPα binds to the Ifng gene and inhibits T-bet-driven Ifng transcription in a DNA binding-dependent manner. Our study thus demonstrates that C/EBPα restricts IFN-γ expression in T cells to allow proper class switching by B cells.


Assuntos
Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Regulação da Expressão Gênica , Interferon gama/genética , Subpopulações de Linfócitos T/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Proteína alfa Estimuladora de Ligação a CCAAT/deficiência , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Perfilação da Expressão Gênica , Imunidade Humoral , Switching de Imunoglobulina , Imunoglobulina G/imunologia , Interferon gama/metabolismo , Camundongos , Camundongos Knockout , Proteínas com Domínio T/metabolismo , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Transcrição Gênica
19.
Proc Natl Acad Sci U S A ; 109(22): 8664-9, 2012 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-22552227

RESUMO

Follicular T-helper (T(FH)) cells cooperate with GL7(+)CD95(+) germinal center (GC) B cells to induce antibody maturation. Herein, we identify the transcription factor IRF4 as a T-cell intrinsic precondition for T(FH) cell differentiation and GC formation. After immunization with protein or infection with the protozoon Leishmania major, draining lymph nodes (LNs) of IFN-regulatory factor-4 (Irf4(-/-)) mice lacked GCs and GC B cells despite developing normal initial hyperplasia. GCs were also absent in Peyer's patches of naive Irf4(-/-) mice. Accordingly, CD4(+) T cells within the LNs and Peyer's patches failed to express the T(FH) key transcription factor B-cell lymphoma-6 and other T(FH)-related molecules. During chronic leishmaniasis, the draining Irf4(-/-) LNs disappeared because of massive cell death. Adoptive transfer of WT CD4(+) T cells or few L. major primed WT T(FH) cells reconstituted GC formation, GC B-cell differentiation, and LN cell survival. In support of a T-cell intrinsic IRF4 activity, Irf4(-/-) T(FH) cell differentiation was not rescued by close neighborhood to transferred WT T(FH) cells. Together with its known B lineage-specific roles during plasma cell maturation and class switch, our study places IRF4 in the center of antibody production toward T-cell-dependent antigens.


Assuntos
Diferenciação Celular/imunologia , Centro Germinativo/imunologia , Fatores Reguladores de Interferon/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Transferência Adotiva , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/transplante , Sobrevivência Celular/imunologia , Feminino , Citometria de Fluxo , Expressão Gênica , Centro Germinativo/citologia , Centro Germinativo/metabolismo , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Interleucinas/genética , Interleucinas/imunologia , Interleucinas/metabolismo , Leishmania major/imunologia , Leishmaniose Cutânea/genética , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/parasitologia , Linfonodos/citologia , Linfonodos/imunologia , Linfonodos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nódulos Linfáticos Agregados/imunologia , Nódulos Linfáticos Agregados/metabolismo , Plasmócitos/imunologia , Plasmócitos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Auxiliares-Indutores/transplante
20.
Immunol Rev ; 241(1): 133-44, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21488895

RESUMO

CD4(+) T cells are the master regulators of adaptive immune responses, and many autoimmune diseases arise due to a breakdown of self-tolerance in CD4(+) T cells. Activation of CD4(+) T cells is regulated by not only the binding of peptide-major histocompatibility complexes to T-cell receptor but also costimulatory signals from antigen-presenting cells. Recently, there has been progress in understanding the extracellular and intracellular mechanisms that are required for implementation and maintenance of T-cell tolerance. Understanding of the molecular mechanisms underlying T-cell tolerance will lead to development of pharmacological approaches either to promote the tolerance state in terms of autoimmunity or to break tolerance in cancer.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Autoantígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Autoimunidade/genética , Linfócitos T CD4-Positivos/metabolismo , Epigênese Genética , Regulação da Expressão Gênica/imunologia , Humanos , Tolerância Imunológica/genética , Ativação Linfocitária/genética , Receptor Cross-Talk/imunologia
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