STAT3 in T helper cell development

STAT3 在 T 辅助细胞发育中的作用

• 批准号: 8354840
• 负责人: MARK H KAPLAN
• 金额: $ 7.79万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8354840
• 关键词: Allergic Disease; Antibody Formation; Asthma; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Bacteria; Binding; CD4 Positive T Lymphocytes; Cell Lineage; Cells; Characteristics; Complex; Cytokine Signaling; Data; Development; Disease; Gene Targeting; Genes; Genetic Programming; Goals; Helper-Inducer T-Lymphocyte; Hypersensitivity; Immune response; Immunity; In Vitro; Inflammation; Inflammatory; Interleukin-13; Interleukin-17; Interleukin-4; Interleukin-5; Mycoses; Parasites; Phenotype; Process; Production; Proteins; Role; STAT protein; STAT3 gene; STAT4 gene; STAT6 gene; Signal Transduction; T-Lymphocyte Subsets; Testing; base; chromatin immunoprecipitation; cytokine; extracellular; genome-wide; in vivo; pathogen; programs; promoter; research study; response; transcription factor

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.

描述（由申请人提供）：CD4+ T 辅助细胞是适应性免疫反应的核心调节因子。 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 辅助细胞谱系都表达赋予特定效应功能的特征性转录因子和细胞因子。效应T辅助细胞亚群的细胞因子分泌潜力需要转录因子的激活和表达，从而促进每个亚群的发育。细胞因子微环境以及启动特定遗传程序的信号转导蛋白和转录激活蛋白 (STAT) 的激活会刺激分化。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，以促进特定 T 辅助细胞亚群的发育。然而，发育中的 Th 亚群会暴露于多种细胞因子。我们最近提供的证据表明，Th 细胞整合多种细胞因子信号的能力对于最佳子集发育是必要的。具体来说，我们证明了 STAT3 单独明显促进 Th17 发育，当它与 STAT6 合作通过结合许多与 STAT6 相同的基因座来编程 Th2 细胞因子表达时，可促进 Th2 分化。在本提案中，我们通过使用染色质免疫沉淀和大规模并行测序来定义 STAT3 在多个 T 细胞亚群中的靶标，测试了 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个信号，并为新范例提供基础，其中单个 STAT 可能是特定表型的关键，而其他 STAT 蛋白合作实现最佳分化和最终免疫反应。 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。该提案研究了导致过敏和自身免疫性疾病相关亚群发展的因素。该项目的完成将使人们对这一过程有更详细的了解，并可能确定治疗这些疾病的新靶点。