STAT4 regulation of effector CD4 T cells and CNS inflammation

STAT4对效应CD4 T细胞和中枢神经系统炎症的调节

• 批准号: 9452007
• 负责人: Laurie Ellen Harrington
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9452007
• 关键词: Apoptosis; Autoimmune Process; CD4 Positive T Lymphocytes; Cell Survival; Cell physiology; Cells; Characteristics; Chronic; Complex; Coupled; Data; Demyelinating Diseases; Development; Disease; Disease susceptibility; Effector Cell; Etiology; Exhibits; Experimental Autoimmune Encephalomyelitis; Future; Gene Activation; Generations; Genes; Genetic Predisposition to Disease; Genetic Transcription; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Immune; Impairment; Individual; Inflammation; Inflammatory; Interferon Type II; Interleukin-12; Laboratories; Lead; Learning; Link; Mediating; Mediator of activation protein; Modeling; Molecular; Multiple Sclerosis; Neuraxis; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Phosphorylation; Predisposition; Process; Production; Property; Publishing; Regulation; Reporting; Role; STAT3 gene; STAT4 gene; STAT4 protein; Shapes; Signal Transduction; Susceptibility Gene; T-Cell Proliferation; Testing; Therapeutic Intervention; United States; cell motility; central nervous system demyelinating disorder; cytokine; design; genetic variant; genome wide association study; inflammatory milieu; interleukin-23; mouse model; novel; prevent; public health relevance; receptor; receptor expression; risk variant

 DESCRIPTION (provided by applicant): Multiple Sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system (CNS) that afflicts over two million individuals worldwide. While the etiology of MS remains unknown, it is clear that there is a genetic predisposition for the disease. Genome-wide association studies indicate a correlation between genetic variants of numerous inflammatory genes and disease susceptibility. Most recently, a susceptibility variant within the intronic sequence of the STAT4 gene was identified. Importantly, expression of the transcription factor STAT4 is essential for the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. These data signify a potentially integral role for STAT4 during the pathogenesis of MS. Currently, the mechanism by which STAT4 mediates CNS inflammation remains elusive; however our own preliminary data show that CD4 T cell intrinsic expression of STAT4 is vital for EAE. Additionally, striking data from our laboratory demonstrates that STAT4 is required for accumulation of CD4 T cells in the inflamed CNS, as well as for the full array of CD4 T cell effector functions. Interestingly, CD4 T cells lacking expression of the IL-23 receptor complex exhibit many of the same characteristics of STAT4 deficient CD4 T cells, and the earliest reports published on IL-23 documented that it induced the phosphorylation of not only STAT3, but also STAT4. STAT4 is also known to regulate expression of IL-12Rß1, one component of the IL-23 receptor complex. Together, the published findings and our preliminary data lead us to hypothesize that IL-23 and STAT4 function in the same pathway in CD4 T cells during EAE, and that STAT4 governs the pathogenic signature in CD4 T cells necessary to confer encephalogenicity during CNS inflammation. To test this, we propose the following specific aims: Aim 1: To determine the impact of STAT4 expression on CD4 T cell functionality during CNS inflammation. Aim 2: To determine the prerequisite of intrinsic STAT4 expression for CD4 T cell accumulation during CNS inflammation. Aim 3: To determine the interplay between STAT4 signaling and the IL-23 pathway in CD4 T cells during CNS inflammation. Collectively, these studies are designed to provide new information regarding the cellular mediators of CNS inflammation during EAE and help to precisely define the properties and molecular regulators which control the development of encephalogenic CD4 T cells. Our long-term goal is elucidate the significance of STAT4 in promoting chronic inflammatory disorders, such as multiple sclerosis, in hopes that a transcriptional target will be identified which can be used for future therapeutic interventions.

 描述（由申请人提供）：多发性硬化症 (MS) 是一种免疫介导的中枢神经系统 (CNS) 脱髓鞘疾病，全世界有超过 200 万人受其困扰。虽然多发性硬化症的病因仍不清楚，但很明显该疾病存在遗传倾向。全基因组关联研究表明许多炎症基因的遗传变异与疾病易感性之间存在相关性。最近，鉴定出 STAT4 基因内含子序列内的易感性变异。重要的是，转录因子 STAT4 的表达对于实验性自身免疫性脑脊髓炎 (EAE)（一种多发性硬化症小鼠模型）的发展至关重要。这些数据表明 STAT4 在 MS 发病机制中潜在的不可或缺的作用。目前，STAT4介导中枢神经系统炎症的机制仍不清楚。然而我们自己的初步数据表明，STAT4 的 CD4 T 细胞内在表达对于 EAE 至关重要。此外，我们实验室的惊人数据表明，STAT4 是发炎中枢神经系统中 CD4 T 细胞积累以及 CD4 T 细胞效应功能的全部所必需的。有趣的是，缺乏 IL-23 受体复合物表达的 CD4 T 细胞表现出许多与 STAT4 缺陷型 CD4 T 细胞相同的特征，最早发表的关于 IL-23 的报告证明，它不仅诱导 STAT3 磷酸化，还诱导 STAT4 磷酸化。 STAT4 还可以调节 IL-12Rß1（IL-23 受体复合物的一个组成部分）的表达。总之，已发表的研究结果和我们的初步数据使我们推测，IL-23 和 STAT4 在 EAE 期间在 CD4 T 细胞中以相同的途径发挥作用，并且 STAT4 控制着 CD4 T 细胞中在 CNS 炎症期间赋予脑源性所必需的致病特征。为了测试这一点，我们提出以下具体目标： 目标 1：确定 CNS 炎症期间 STAT4 表达对 CD4 T 细胞功能的影响。 目标 2：确定中枢神经系统炎症期间 CD4 T 细胞积累的内在 STAT4 表达的先决条件。 目标 3：确定 CNS 炎症期间 CD4 T 细胞中 STAT4 信号传导与 IL-23 通路之间的相互作用。总的来说，这些研究旨在提供有关 EAE 期间中枢神经系统炎症细胞介质的新信息，并有助于精确定义控制脑源性 CD4 T 细胞发育的特性和分子调节因子。我们的长期目标是阐明 STAT4 在促进多发性硬化症等慢性炎症性疾病中的重要性，希望能够鉴定出可用于未来治疗干预的转录靶标。