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1.
Nat Immunol ; 15(6): 571-9, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24777532

RESUMO

Intestinal regulatory T cells (Treg cells) are necessary for the suppression of excessive immune responses to commensal bacteria. However, the molecular machinery that controls the homeostasis of intestinal Treg cells has remained largely unknown. Here we report that colonization of germ-free mice with gut microbiota upregulated expression of the DNA-methylation adaptor Uhrf1 in Treg cells. Mice with T cell-specific deficiency in Uhrf1 (Uhrf1(fl/fl)Cd4-Cre mice) showed defective proliferation and functional maturation of colonic Treg cells. Uhrf1 deficiency resulted in derepression of the gene (Cdkn1a) that encodes the cyclin-dependent kinase inhibitor p21 due to hypomethylation of its promoter region, which resulted in cell-cycle arrest of Treg cells. As a consequence, Uhrf1(fl/fl)Cd4-Cre mice spontaneously developed severe colitis. Thus, Uhrf1-dependent epigenetic silencing of Cdkn1a was required for the maintenance of gut immunological homeostasis. This mechanism enforces symbiotic host-microbe interactions without an inflammatory response.


Assuntos
Colite/imunologia , Colo/imunologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Epigênese Genética , Proteínas Nucleares/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Proteínas Estimuladoras de Ligação a CCAAT , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Células Cultivadas , Clostridium/imunologia , Colite/genética , Colo/microbiologia , Metilação de DNA , Perfilação da Expressão Gênica , Interleucina-2 , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microbiota/imunologia , Proteínas Nucleares/biossíntese , Proteínas Nucleares/genética , Regiões Promotoras Genéticas , Interferência de RNA , RNA Interferente Pequeno , Simbiose/imunologia , Ubiquitina-Proteína Ligases , Regulação para Cima
2.
Nature ; 585(7823): 102-106, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32848245

RESUMO

Accumulating evidence indicates that gut microorganisms have a pathogenic role in autoimmune diseases, including in multiple sclerosis1. Studies of experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis)2,3, as well as human studies4-6, have implicated gut microorganisms in the development or severity of multiple sclerosis. However, it remains unclear how gut microorganisms act on the inflammation of extra-intestinal tissues such as the spinal cord. Here we show that two distinct signals from gut microorganisms coordinately activate autoreactive T cells in the small intestine that respond specifically to myelin oligodendrocyte glycoprotein (MOG). After induction of experimental autoimmune encephalomyelitis in mice, MOG-specific CD4+ T cells are observed in the small intestine. Experiments using germ-free mice that were monocolonized with microorganisms from the small intestine demonstrated that a newly isolated strain in the family Erysipelotrichaceae acts similarly to an adjuvant to enhance the responses of T helper 17 cells. Shotgun sequencing of the contents of the small intestine revealed a strain of Lactobacillus reuteri that possesses peptides that potentially mimic MOG. Mice that were co-colonized with these two strains showed experimental autoimmune encephalomyelitis symptoms that were more severe than those of germ-free or monocolonized mice. These data suggest that the synergistic effects that result from the presence of these microorganisms should be considered in the pathogenicity of multiple sclerosis, and that further study of these microorganisms may lead to preventive strategies for this disease.


Assuntos
Encefalomielite Autoimune Experimental/microbiologia , Microbioma Gastrointestinal/imunologia , Inflamação/patologia , Medula Espinal/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/prevenção & controle , Feminino , Vida Livre de Germes , Inflamação/imunologia , Intestino Delgado/imunologia , Intestino Delgado/microbiologia , Intestino Delgado/patologia , Limosilactobacillus reuteri/química , Limosilactobacillus reuteri/imunologia , Limosilactobacillus reuteri/patogenicidade , Masculino , Camundongos , Esclerose Múltipla/imunologia , Esclerose Múltipla/microbiologia , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito/química , Glicoproteína Mielina-Oligodendrócito/imunologia , Medula Espinal/imunologia , Células Th17/imunologia , Células Th17/patologia
3.
Nature ; 504(7480): 446-50, 2013 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-24226770

RESUMO

Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (Treg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic Treg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of Treg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of Treg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4(+) CD45RB(hi) T cells in Rag1(-/-) mice. Treatment of naive T cells under the Treg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of Treg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.


Assuntos
Butiratos/metabolismo , Diferenciação Celular , Colo/imunologia , Colo/microbiologia , Fermentação , Simbiose , Linfócitos T Reguladores/citologia , Acetilação/efeitos dos fármacos , Transferência Adotiva , Animais , Butiratos/análise , Butiratos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Colite/tratamento farmacológico , Colite/patologia , Colo/citologia , Colo/metabolismo , Sequência Conservada , Feminino , Fatores de Transcrição Forkhead/genética , Vida Livre de Germes , Histonas/metabolismo , Homeostase/efeitos dos fármacos , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Contagem de Linfócitos , Espectroscopia de Ressonância Magnética , Masculino , Metaboloma , Camundongos , Regiões Promotoras Genéticas/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
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