TLR-mediated control of adaptive immunity and peripheral tolerance.

摘要

Toll-like receptors (TLRs) play a critical role in host resistance against a diverse repertoire of microbial infections. Although it is known that TLRs are important for the initiation of adaptive immune responses, the molecular mechanisms of TLR-mediated control of adaptive immunity are still not fully understood. By generating mice that carry a T cell-specific deletion of the IL-6 receptor alpha chain (IL-6Ralpha T-KO mice), we show that LPS-induced IL-6 is essential for CD4+ T cell activation, Th1 responses and differentiation of Th17 and follicular helper T (Tfh) cells in vivo. We demonstrate that transient depletion of regulatory T cells (Tregs) recovers Th1 responses in IL-6Ralpha T-KO mice and ablation of the IL-6Ralpha chain specifically in Tregs had no effect on the CD4+ T cell response, suggesting that IL-6 acts on naive T cells in order to block their suppression by Tregs. In addition, we show that IL-6 signaling in T cells is required for the generation of memory CD4+ T cell responses. These data thus demonstrate that IL-6 is required for CD4+ T cell responses on multiple levels including activation, differentiation, and memory formation following LPS immunization and presumably bacterial infection. However, we found that IL-6 was dispensable for Th1 responses following poly(I:C) immunization and viral infection. We also found that the Th1 cells generated under these conditions, unlike LPS-induced Th1 cells, expressed the cytotoxic mediator Fas ligand (FasL), suggesting that there might be a specialized Th1 subset dedicated to antiviral defense. Furthermore, we found that antigen administration in the absence of TLR activation leads to antigen-specific long-lived CD4+ T cell unresponsiveness, which was controlled by Tregs. We found that Tregs were required at the time of antigen administration for the induction and maintenance of tolerance. DCs also play an important role in tolerance induction in the steady state. However, the maturation state, origin and phenotype of tolerogenic DCs remain poorly understood. We have characterized a population of tolerogenic DCs and have identified molecular factors that distinguish these cells from immunogenic DCs and might be important for their generation. Collectively, these studies contribute to our knowledge of the molecular mechanisms by which TLRs control adaptive immunity and also reveal a fundamental role for Tregs in the induction and maintenance of T cell tolerance. Furthermore, our study will hopefully lead to a better understanding of the phenotype and function of the elusive steady state tolerogenic DCs.