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应答的中心调节因子。CD4+ T辅助细胞分化成几个不同的亚群，为宿主提供针对多种病原体的保护。每个T辅助细胞谱系表达赋予特定效应子功能的特征性转录因子和细胞因子。效应性T辅助细胞亚群的精氨酸分泌潜力需要转录因子的激活和表达，这些转录因子促进每个亚群的发育。细胞因子微环境和启动特定遗传程序的信号转导和转录激活因子（STAT）蛋白的激活刺激分化。一个简单的范例表明，需要一个单一的STAT蛋白激活的细胞因子，促进特定的T辅助细胞亚群的发展。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是必要的最佳子集的发展。具体地说，我们证明，STAT3，这显然促进Th17的发展，在隔离，促进Th2分化时，它与STAT6在编程Th2细胞因子的表达，结合到许多相同的基因座STAT6。在这个建议中，我们测试的假设，即STAT3结合到共同的和独特的基因之间的Th亚群，通过使用染色质免疫沉淀和大规模平行测序，以确定在多个T细胞亚群中的STAT3的目标。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，并为新的范例提供基础，其中单个STAT可能是特定表型的关键，而其他STAT蛋白质合作以实现最佳分化并最终实现免疫应答。

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.