RESUMO
Dendritic cells (DCs) play a pivotal role in controlling the balance between tolerance and immunity in the intestine. Gut conditioned CD103(+) DCs promote regulatory T (Treg) cell responses; however, little is known about DCs that drive inflammation in the intestine. Here, we show that monocyte-derived inflammatory DCs that express E-cadherin, the receptor for CD103, promote intestinal inflammation. E-cadherin(+) DCs accumulated in the inflamed mesenteric lymph nodes and colon, had high expression of toll-like receptors, and produced colitogenic cytokines, such as IL-6 and IL-23, after activation. Importantly, adoptive transfer of E-cadherin(+) DCs into T cell-restored immunodeficient hosts increased Th17 cell responses in the intestine and led to exacerbation of colitis. These results identify a monocyte-derived inflammatory DC subset that is associated with the pathogenesis of intestinal inflammation, providing a therapeutic target for the treatment of inflammatory bowel disease.
Assuntos
Caderinas/imunologia , Colite/imunologia , Células Dendríticas/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD/imunologia , Antígeno CD11c/imunologia , Diferenciação Celular , Movimento Celular , Colite/genética , Colite/patologia , Células Dendríticas/citologia , Regulação da Expressão Gênica , Imunidade Inata , Inflamação/imunologia , Cadeias alfa de Integrinas/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/citologia , Monócitos/imunologiaRESUMO
Foxp3(+) regulatory T (T reg) cells play a key role in controlling immune pathological re actions. Many develop their regulatory activity in the thymus, but there is also evidence for development of Foxp3(+) T reg cells from naive precursors in the periphery. Recent studies have shown that transforming growth factor (TGF)-beta can promote T reg cell development in culture, but little is known about the cellular and molecular mechanisms that mediate this pathway under more physiological conditions. Here, we show that after antigen activation in the intestine, naive T cells acquire expression of Foxp3. Moreover, we identify a population of CD103(+) mesenteric lymph node dendritic cells (DCs) that induce the development of Foxp3(+) T reg cells. Importantly, promotion of T reg cell responses by CD103(+) DCs is dependent on TGF-beta and the dietary metabolite, retinoic acid (RA). These results newly identify RA as a cofactor in T reg cell generation, providing a mechanism via which functionally specialized gut-associated lymphoid tissue DCs can extend the repertoire of T reg cells focused on the intestine.
Assuntos
Antígenos CD/biossíntese , Células Dendríticas/metabolismo , Fatores de Transcrição Forkhead/fisiologia , Cadeias alfa de Integrinas/biossíntese , Linfócitos T/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Tretinoína/metabolismo , Animais , Linfócitos T CD4-Positivos/metabolismo , Separação Celular , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Camundongos Transgênicos , Modelos BiológicosRESUMO
Intestinal CD103(+) DC promote the differentiation of Foxp3(+) Treg from naïve CD4(+) T cells through mechanisms involving TGF-beta and the dietary metabolite, retinoic acid (RA). In this study, we have analysed whether the specialised features of CD103(+) DC are conserved in colitis. Our results show that inflammation dampens the tolerogenic properties of MLN CD103(+) DC, which is associated with lower expression of tgfbeta2 and aldh1a2. Accordingly, CD103(+) DC taken from colitic mice are impaired in their ability to induce Foxp3(+) Treg and instead favour the emergence of IFN-gamma-producing CD4(+) T cells compared with their steady-state counterparts. BrdU-labelling studies and analysis of ontogeny markers show that CD103(+) DC from steady-state and colitic settings retain similar subset composition and developmental pathways. These results indicate that MLN CD103(+) DC are not hard-wired to promote tolerance but can adapt to environmental conditions. The inflammatory properties of MLN CD103(+) DC in colitic mice may reflect defective gut tolerogenic conditioning or altered migratory pathways and raise the possibility that migratory DC populations contribute to the pathogenesis of inflammatory bowel disease.