Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Clin Invest ; 129(3): 1257-1271, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30741720

RESUMO

Tregs play a fundamental role in immune tolerance via control of self-reactive effector T cells (Teffs). This function is dependent on maintenance of a high intracellular cAMP concentration. A number of microRNAs are implicated in the maintenance of Tregs. In this study, we demonstrate that peripheral immune tolerance is critically dependent on posttranscriptional repression of the cAMP-hydrolyzing enzyme phosphodiesterase-3b (Pde3b) by microRNA-142-5p (miR-142-5p). In this manner, miR-142-5p acts as an immunometabolic regulator of intracellular cAMP, controlling Treg suppressive function. Mir142 was associated with a super enhancer bound by the Treg lineage-determining transcription factor forkhead box P3 (FOXP3), and Treg-specific deletion of miR-142 in mice (TregΔ142) resulted in spontaneous, lethal, multisystem autoimmunity, despite preserved numbers of phenotypically normal Tregs. Pharmacological inhibition and genetic ablation of PDE3B prevented autoimmune disease and reversed the impaired suppressive function of Tregs in TregΔ142 animals. These findings reveal a critical molecular switch, specifying Treg function through the modulation of a highly conserved, cell-intrinsic metabolic pathway. Modulation of this pathway has direct relevance to the pathogenesis and treatment of autoimmunity and cancer.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/imunologia , Regulação Enzimológica da Expressão Gênica/imunologia , Tolerância Imunológica , MicroRNAs/imunologia , Sistemas do Segundo Mensageiro/imunologia , Linfócitos T Reguladores/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , AMP Cíclico/genética , AMP Cíclico/imunologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Regulação Enzimológica da Expressão Gênica/genética , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , Sistemas do Segundo Mensageiro/genética , Linfócitos T Reguladores/patologia
2.
Nat Immunol ; 16(2): 207-213, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25531831

RESUMO

Lymphocyte recruitment maintains intestinal immune homeostasis but also contributes to inflammation. The orphan chemoattractant receptor GPR15 mediates regulatory T cell homing and immunosuppression in the mouse colon. We show that GPR15 is also expressed by mouse TH17 and TH1 effector cells and is required for colitis in a model that depends on the trafficking of these cells to the colon. In humans GPR15 is expressed by effector cells, including pathogenic TH2 cells in ulcerative colitis, but is expressed poorly or not at all by colon regulatory T (Treg) cells. The TH2 transcriptional activator GATA-3 and the Treg-associated transcriptional repressor FOXP3 robustly bind human, but not mouse, GPR15 enhancer sequences, correlating with receptor expression. Our results highlight species differences in GPR15 regulation and suggest it as a potential therapeutic target for colitis.


Assuntos
Colite/fisiopatologia , Colo/fisiopatologia , Regulação da Expressão Gênica , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Retorno de Linfócitos/metabolismo , Receptores de Peptídeos/metabolismo , Animais , Células Cultivadas , Colite/imunologia , Colo/imunologia , Modelos Animais de Doenças , Elementos Facilitadores Genéticos/genética , Fatores de Transcrição Forkhead/metabolismo , Técnicas de Inativação de Genes , Humanos , Camundongos , Ligação Proteica , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genética , Especificidade da Espécie
3.
J Immunol ; 191(12): 5925-32, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24249732

RESUMO

The complex relationship between Th1 and Th17 cells is incompletely understood. The transcription factor T-bet is best known as the master regulator of Th1 lineage commitment. However, attention is now focused on the repression of alternate T cell subsets mediated by T-bet, particularly the Th17 lineage. It has recently been suggested that pathogenic Th17 cells express T-bet and are dependent on IL-23. However, T-bet has previously been shown to be a negative regulator of Th17 cells. We have taken an unbiased approach to determine the functional impact of T-bet on Th17 lineage commitment. Genome-wide analysis of functional T-bet binding sites provides an improved understanding of the transcriptional regulation mediated by T-bet, and suggests novel mechanisms by which T-bet regulates Th cell differentiation. Specifically, we show that T-bet negatively regulates Th17 lineage commitment via direct repression of the transcription factor IFN regulatory factor-4 (IRF4). An in vivo analysis of the pathogenicity of T-bet-deficient T cells demonstrated that mucosal Th17 responses were augmented in the absence of T-bet, and we have demonstrated that the roles of T-bet in enforcing Th1 responses and suppressing Th17 responses are separable. The interplay of the two key transcription factors T-bet and IRF4 during the determination of T cell fate choice significantly advances our understanding of the mechanisms underlying the development of pathogenic T cells.


Assuntos
Regulação da Expressão Gênica/imunologia , Fatores Reguladores de Interferon/antagonistas & inibidores , Linfopoese/genética , Proteínas com Domínio T/fisiologia , Células Th17/citologia , Transcrição Gênica , Transferência Adotiva , Animais , Sítios de Ligação , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Células Cultivadas , Quimera , Colite/imunologia , Proteínas de Ligação a DNA/deficiência , Feminino , Genes Reporter , Vetores Genéticos , Estudo de Associação Genômica Ampla , Fatores Reguladores de Interferon/biossíntese , Fatores Reguladores de Interferon/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas com Domínio T/genética
4.
Ann Intern Med ; 158(6): 469-77, 2013 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-23552405

RESUMO

It has been 20 years since the first description of a rapidly progressive renal disease that is associated with the consumption of Chinese herbs containing aristolochic acid (AA) and is now termed aristolochic acid nephropathy (AAN). Recent data have shown that AA is also the primary causative agent in Balkan endemic nephropathy and associated urothelial cancer. Aristolochic acid nephropathy is associated with a high long-term risk for renal failure and urothelial cancer, and the potential worldwide population exposure is enormous. This evidence-based review of the diagnostic approach to and management of AAN draws on the authors' experience with the largest and longest-studied combined cohort of patients with this condition. It is hoped that a better understanding of the importance of this underrecognized and severe condition will improve epidemiologic, preventive, and therapeutic strategies to reduce the global burden of this disease.


Assuntos
Ácidos Aristolóquicos/efeitos adversos , Nefropatias/induzido quimicamente , Preparações de Plantas/efeitos adversos , Nefropatia dos Bálcãs/induzido quimicamente , Nefropatia dos Bálcãs/diagnóstico , Nefropatia dos Bálcãs/epidemiologia , Nefropatia dos Bálcãs/terapia , Humanos , Nefropatias/diagnóstico , Nefropatias/epidemiologia , Nefropatias/fisiopatologia , Nefropatias/terapia , Fatores de Risco , Neoplasias Urológicas/induzido quimicamente , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/epidemiologia , Neoplasias Urológicas/fisiopatologia , Neoplasias Urológicas/terapia
5.
Nat Commun ; 3: 1268, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23232398

RESUMO

T-bet and GATA3 regulate the CD4+ T cell Th1/Th2 cell fate decision but little is known about the interplay between these factors outside of the murine Ifng and Il4/Il5/Il13 loci. Here we show that T-bet and GATA3 bind to multiple distal sites at immune regulatory genes in human effector T cells. These sites display markers of functional elements, act as enhancers in reporter assays and are associated with a requirement for T-bet and GATA3. Furthermore, we demonstrate that both factors bind distal sites at Tbx21 and that T-bet directly activates its own expression. We also show that in Th1 cells, GATA3 is distributed away from Th2 genes, instead occupying T-bet binding sites at Th1 genes, and that T-bet is sufficient to induce GATA3 binding at these sites. We propose these aspects of T-bet and GATA3 function are important for Th1/Th2 differentiation and for understanding transcription factor interactions in other T cell lineage decisions.


Assuntos
Fator de Transcrição GATA3/fisiologia , Proteínas com Domínio T/fisiologia , Células Th1/fisiologia , Células Th2/fisiologia , Animais , Sítios de Ligação/fisiologia , Linfócitos T CD4-Positivos/fisiologia , Diferenciação Celular/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Análise de Sequência com Séries de Oligonucleotídeos , Sequências Reguladoras de Ácido Nucleico
6.
Immunity ; 37(4): 674-84, 2012 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-23063332

RESUMO

Mice lacking the transcription factor T-bet in the innate immune system develop microbiota-dependent colitis. Here, we show that interleukin-17A (IL-17A)-producing IL-7Rα(+) innate lymphoid cells (ILCs) were potent promoters of disease in Tbx21(-/-)Rag2(-/-) ulcerative colitis (TRUC) mice. TNF-α produced by CD103(-)CD11b(+) dendritic cells synergized with IL-23 to drive IL-17A production by ILCs, demonstrating a previously unrecognized layer of cellular crosstalk between dendritic cells and ILCs. We have identified Helicobacter typhlonius as a key disease trigger driving excess TNF-α production and promoting colitis in TRUC mice. Crucially, T-bet also suppressed the expression of IL-7R, a key molecule involved in controlling intestinal ILC homeostasis. The importance of IL-7R signaling in TRUC disease was highlighted by the dramatic reduction in intestinal ILCs and attenuated colitis following IL-7R blockade. Taken together, these data demonstrate the mechanism by which T-bet regulates the complex interplay between mucosal dendritic cells, ILCs, and the intestinal microbiota.


Assuntos
Colite Ulcerativa/imunologia , Proteínas de Ligação a DNA/imunologia , Imunidade Inata , Linfócitos/imunologia , Receptores de Interleucina-7/imunologia , Proteínas com Domínio T/imunologia , Animais , Células Cultivadas , Doença Crônica , Colite Ulcerativa/microbiologia , Colite Ulcerativa/patologia , Proteínas de Ligação a DNA/deficiência , Helicobacter/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Transdução de Sinais , Proteínas com Domínio T/deficiência
8.
Curr Opin Immunol ; 20(5): 568-74, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18655831

RESUMO

The immune system mounts a response to non-self transplanted tissue through a number of mechanisms. The indirect pathway of allorecognition, in which cells of the adaptive immune system recognize MHC alloantigen-derived peptide on self-MHC molecules, has emerged as a potent inducer of allograft rejection. In particular, recent evidence convincingly connects the indirect pathway with chronic rejection, including antibody-mediated and CD8(+) T cell-mediated rejection. However, the indirect pathway can also promote the generation of regulatory T cells, which have emerged as crucial suppressors of the alloresponse, and hold much promise in the quest for clinical tolerance. An improved understanding of the indirect pathway is likely to bring important benefits to transplant recipients.


Assuntos
Rejeição de Enxerto/imunologia , Antígenos de Histocompatibilidade/imunologia , Tolerância Imunológica/imunologia , Linfócitos T Reguladores/imunologia , Imunologia de Transplantes , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Antígenos de Histocompatibilidade/metabolismo , Humanos , Isoantígenos/imunologia , Linfócitos T Reguladores/metabolismo , Transplante Homólogo/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...