STAT3 in T helper cell development

描述(申请人提供)：CD4+T辅助细胞是适应性免疫反应的中心调节细胞。CD4+T辅助细胞分化为几个不同的亚群，以提供对各种病原体的宿主保护。每个T辅助细胞谱系都表达特有的转录因子和细胞因子，这些因子赋予特定的效应器功能。效应T辅助细胞亚群的细胞因子分泌能力需要转录因子的激活和表达，以促进每个亚群的发育。分化受到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蛋白(STAT)的激活的刺激。一个简单的范例表明，需要一个由细胞因子激活的单一STAT蛋白，该细胞因子促进特定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最佳亚集发育所必需的。具体地说，我们证明了STAT3，明显促进Th17的单独发育，当它与STAT6合作编程Th2细胞因子表达时，通过与许多与STAT6相同的基因座结合，促进Th2分化。在这个方案中，我们通过染色质免疫沉淀和大规模并行测序来确定STAT3在多个T细胞亚群中的靶点，从而验证了STAT3与Th亚群中共同和独特的基因结合的假设。这些研究将确定发育中的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蛋白相互协作以实现最佳分化和最终的免疫反应。 公共卫生相关性：炎症性疾病的发展取决于T细胞亚群的功能。这项建议研究了与过敏性和自身免疫性疾病有关的亚群的形成因素。该项目的完成将导致对这一过程有更详细的了解，并可能为这些疾病的治疗确定新的目标。

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. PUBLIC HEALTH RELEVANCE: The development of inflammatory disease depends upon the function of subsets of T cells. This proposal examines the factors that contribute to the development of subsets that are involved in allergic and autoimmune disease. The completion of this project will result in a more detailed understanding of this process, and may identify new targets for the treatment of these diseases.