RESUMEN
Although the physiologic pathways that control regulatory T cells (Foxp3-expressing regulatory T cells, IL-10-secreting Tr1 cells) and Th17 cells in rodents have been defined, the factors that control these differentiation pathways in humans are not well understood. In this study, we show that IL-27 promotes the differentiation of IL-10-secreting Tr1 cells while inhibiting Th17 generation and molecules associated with Th17 function. Furthermore, IL-27 inhibits IL-17-polarizing cytokines on dendritic cells, which in turn decrease IL-17 secretion from T cells. Our results demonstrate that IL-27 plays a key role in human T cells by promoting IL-10-secreting Tr1 cells and inhibiting Th17 cells and thus provides a dual regulatory mechanism to control autoimmunity and tissue inflammation.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Interleucina-10/biosíntesis , Interleucina-17/biosíntesis , Interleucinas/fisiología , Enfermedades Autoinmunes/patología , Enfermedades Autoinmunes/prevención & control , Linfocitos T CD4-Positivos/patología , Comunicación Celular/inmunología , Polaridad Celular/inmunología , Proliferación Celular , Células Cultivadas , Técnicas de Cocultivo , Retroalimentación Fisiológica/inmunología , Inhibidores de Crecimiento/fisiología , Humanos , Inmunofenotipificación , Mediadores de Inflamación/fisiología , Interleucina-10/metabolismo , Interleucina-10/fisiología , Interleucina-17/antagonistas & inhibidores , Interleucina-17/fisiología , Activación de Linfocitos/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patologíaRESUMEN
Therapeutic strategies for multiple sclerosis have radically changed in the past 15 years. Five regulatory-approved immunomodulatory agents are reasonably effective in the treatment of relapsing-remitting multiple sclerosis, and appear to delay the time to progression to disabling stages. Inhibiting disease progression remains the central challenge for the development of improved therapies. As understanding of the immunopathogenesis of multiple sclerosis has advanced, a number of novel potential therapeutics have been identified, and are discussed here. It has also become apparent that traditional views of multiple sclerosis simply as a CD4+ T-cell-mediated disease of the central nervous system are incomplete. The pathogenic role of other immune components such as the innate immune system, regulatory T cells, T helper 17 cells and B cells is reaching centre stage, opening up exciting avenues and novel potential targets to affect the natural course of multiple sclerosis.