STAT3 in T helper cell development

描述（由申请人提供）：CD4+ T辅助细胞是适应性免疫反应的中枢调节因子。CD4+辅助性T细胞分化成几个不同的亚群，为宿主提供针对各种病原体的保护。每种辅助性T细胞谱系表达特有的转录因子和细胞因子，赋予特定的效应功能。效应T辅助亚群的细胞因子分泌潜能需要激活和表达促进每个亚群发育的转录因子。分化是由细胞因子微环境和启动特定遗传程序的信号换能器和转录激活因子（STAT）蛋白的激活刺激的。一个简单的范例表明，需要一个由细胞因子激活的STAT蛋白来促进特定T辅助亚群的发展。然而，发育中的Th亚群暴露于多种细胞因子。我们最近提供的证据表明，Th细胞整合来自多种细胞因子的信号的能力对于最佳亚群发育是必要的。具体来说，我们证明了STAT3在分离时明显促进Th17的发育，当它与STAT6合作，通过结合许多与STAT6相同的位点来编程Th2细胞因子表达时，它促进了Th2的分化。在本研究中，我们通过染色质免疫沉淀和大量平行测序来确定STAT3在多个T细胞亚群中的靶标，从而验证了STAT3与Th亚群中常见和独特基因结合的假设。这些研究将定义发育中的Th细胞如何在转录因子结合水平上整合多种信号，并为一个新的范式提供基础，其中单个STAT可能是特定表型的关键，而其他STAT蛋白合作实现最佳分化和最终免疫反应。

DESCRIPTION (provided by applicant): CD4+ T helper cells are central regulators of adaptive immune responses. CD4+ T helper cells differentiate into several distinct subsets to provide host protection against a variety of pathogens. Each T helper cell lineage expresses characteristic transcription factors and cytokines that confer specific effector functions. The cytokine-secreting potential of effector T helper subsets requires the activation and expression of transcription factors that promote the development of each subset. Differentiation is stimulated by the cytokine microenvironment and the activation of Signal Transducer and Activator of Transcription (STAT) proteins that initiate specific genetic programs. A simple paradigm suggested the requirement for a single STAT protein activated by a cytokine that promoted the development of a specific T helper subset. However, developing Th subsets are exposed to multiple cytokines. We have recently provided evidence that the ability of Th cells to integrate signals from multiple cytokines is necessary for optimal subset development. Specifically, we demonstrated that STAT3, which clearly promotes Th17 development in isolation, promotes Th2 differentiation when it cooperates with STAT6 in programming Th2 cytokine expression by binding to many of the same loci as STAT6. In this proposal we test the hypothesis that STAT3 binds to common and unique genes among Th subsets by using chromatin immunoprecipitation and massive parallel sequencing to define the targets of STAT3 in multiple T cell subsets. These studies will define how a developing Th cell integrates multiple signals at the level of transcription factor binding and provide the basis for a new paradigm wherein a single STAT may be the key to a particular phenotype, whereas other STAT proteins cooperate to achieve optimal differentiation and ultimately immune responses.