Role of Cytokines in Naive CD4+ T cell Activation

描述（由申请人提供）：本提案的总体目标是阐明细胞因子在体内抗原驱动的初始CD 4 + T细胞活化中的作用。尽管IL-2在体外初始T细胞增殖的引发中的作用已被充分确立，但越来越多的证据表明，在体内，IL-2不是该过程所必需的。我们的假设是，最佳的抗原驱动的幼稚CD 4 + T细胞的增殖在体内由γ共同依赖性细胞因子激活的StatS信号和gp 130依赖性细胞因子激活的Stat 5信号冗余地促进。使用能够在抗原刺激之前对初始CD 4 + T细胞进行遗传操作的体内实验系统，这些候选细胞因子的信号传导功能将被阻断以评估它们在促进增殖和发育成Th效应细胞中的作用。这种策略将避免这些细胞因子在T细胞发育的其他阶段中的多效性作用所引起的并发症，这破坏了对过去体内研究的解释。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to clarify the role of cytokines in antigen-driven naive CD4+ T cell activation in vivo. Despite the well established role of IL-2 in the priming of naive T cell proliferation in vitro, growing evidence suggests that in vivo, IL-2 is not required for this process. Our hypothesis is that optimal antigen-driven proliferation of naive CD4+ T cells is promoted redundantly in vivo by StatS signals activated by gamma common-dependent cytokines, and Stat5 signals activated by gp130-dependent cytokines. Using an in vivo experimental system that enables genetic manipulation of naive CD4+ T cells just prior to antigen stimulation, the signaling functions of these candidate cytokines will be blocked to assess their role in promoting proliferation and development into Th effector cells. This strategy will avoid complications arising from the pleiotropic roles of these cytokines in other stages of T cell development, which have undermined interpretations of past in vivo studies.