RESUMEN
Colonization with a mixture of Clostridium species has been shown to induce accumulation of induced regulatory T (iTreg) cells in the colon. Transforming growth factor-ß (TGF-ß) is an essential factor for iTreg cell induction; however, the relationship between Clostridium species and TGF-ß remains to be clarified. Here we demonstrated that a gram-positive probiotic bacterial strain, Clostridium butyricum (C. butyricum), promoted iTreg cell generation in the intestine through induction of TGF-ß1 from lamina propria dendritic cells (LPDCs). C. butyricum-mediated TGF-ß1 induction was mainly Toll-like receptor 2 (TLR2) dependent, and the ERK-AP-1 kinase pathway played an important role. In addition, the autocrine TGF-ß-Smad3 transcription factor signal was necessary for robust TGF-ß expression in DCs, whereas Smad2 negatively regulated TGF-ß expression. Smad2-deficient DCs expressed higher concentrations of TGF-ß and were tolerogenic for colitis models. This study reveals a novel mechanism of TGF-ß induction by Clostridia through a cooperation between TLR2-AP-1 and TGF-ß-Smad signaling pathways.
Asunto(s)
Clostridium butyricum/inmunología , Células Dendríticas/inmunología , Proteína Smad2/genética , Proteína smad3/genética , Factor de Crecimiento Transformador beta1/biosíntesis , Animales , Infecciones por Clostridium/inmunología , Infecciones por Clostridium/microbiología , Colitis/inmunología , Quinasas MAP Reguladas por Señal Extracelular/inmunología , Intestinos/inmunología , Intestinos/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Membrana Mucosa/citología , Membrana Mucosa/inmunología , Regiones Promotoras Genéticas/genética , Linfocitos T Reguladores/inmunología , Receptor Toll-Like 2/inmunología , Factor de Transcripción AP-1/inmunología , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
Regulatory T cells (T(reg) cells) develop from progenitor thymocytes after the engagement of T cell antigen receptors (TCRs) with high-affinity ligands, but the underlying molecular mechanisms are still unclear. Here we show that the Nr4a nuclear receptors, which are encoded by immediate-early genes upregulated by TCR stimulation in thymocytes, have essential roles in T(reg) cell development. Mice that lacked all Nr4a factors could not produce T(reg) cells and died early owing to systemic autoimmunity. Nr4a receptors directly activated the promoter of the gene encoding the transcription factor Foxp3, and forced activation of Nr4a receptors bypassed low-strength TCR signaling to drive the T(reg) cell developmental program. Our results suggest that Nr4a receptors have key roles in determining CD4(+) T cell fates in the thymus and thus contribute to immune homeostasis.
Asunto(s)
Proteínas de Unión al ADN/fisiología , Proteínas del Tejido Nervioso/fisiología , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/fisiología , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/fisiología , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Esteroides/fisiología , Receptores de Hormona Tiroidea/fisiología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Autoinmunidad/genética , Diferenciación Celular , Células Cultivadas , Proteínas de Unión al ADN/genética , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Genes Inmediatos-Precoces , Homeostasis , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Regiones Promotoras Genéticas , Interferencia de ARN , ARN Interferente Pequeño , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Esteroides/genética , Receptores de Hormona Tiroidea/genética , Transducción de Señal , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/citología , Timocitos/metabolismoRESUMEN
Regulatory T cells (Tregs) have a central role in maintaining immune homoeostasis through various mechanisms. Although the Forkhead transcription factor Foxp3 defines the Treg cell lineage and functions, the molecular mechanisms of Foxp3 induction and maintenance remain elusive. Here we show that Foxp3 is one of the direct targets of Nr4a2. Nr4a2 binds to regulatory regions of Foxp3, where it mediates permissive histone modifications. Ectopic expression of Nr4a2 imparts Treg-like suppressive activity to naïve CD4(+) T cells by inducing Foxp3 and by repressing cytokine production, including interferon-γ and interleukin-2. Deletion of Nr4a2 in T cells attenuates induction of Tregs and causes aberrant induction of Th1, leading to the exacerbation of colitis. Nr4a2-deficeint Tregs are prone to lose Foxp3 expression and have attenuated suppressive ability both in vitro and in vivo. Thus, Nr4a2 has the ability to maintain T-cell homoeostasis by regulating induction, maintenance and suppressor functions of Tregs, and by repression of aberrant Th1 induction.
