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CD4+ T细胞活化中的作用。尽管IL-2在体外启动初始T细胞增殖中的作用已经得到了很好的证实，但越来越多的证据表明，在体内，这一过程并不需要IL-2。我们的假设是，由γ共同依赖的细胞因子激活的StatS信号和gp130依赖的细胞因子激活的Stat5信号，在体内冗余地促进了初始CD4+ T细胞的最佳抗原驱动增殖。使用体内实验系统，在抗原刺激之前对初始CD4+ T细胞进行遗传操作，这些候选细胞因子的信号功能将被阻断，以评估它们在促进增殖和发育为效应细胞中的作用。这一策略将避免由于这些细胞因子在T细胞发育的其他阶段的多效性作用而引起的并发症，这些并发症破坏了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.