STAT4 regulation of effector CD4 T cells and CNS inflammation

 描述(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，困扰着全球200多万人。虽然多发性硬化症的病因仍不清楚，但很明显，这种疾病有遗传易感性。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，在STAT4基因的内含子序列中发现了一个易感变异。重要的是，转录因子STAT4的表达在MS小鼠模型实验性自身免疫性脑脊髓炎(EAE)的发生发展中是必不可少的。这些数据表明，STAT4在MS的发病机制中可能起着不可或缺的作用。目前，STAT4介导中枢神经系统炎症的机制仍然不清楚；然而，我们自己的初步数据表明，CD4T细胞固有的STAT4表达对EAE至关重要。此外，来自我们实验室的惊人数据表明，STAT4对于炎症的中枢神经系统中CD4T细胞的积累以及完整的CD4T细胞效应器功能是必需的。有趣的是，缺乏IL-23受体复合体表达的CD4T细胞表现出许多与STAT4缺陷的CD4T细胞相同的特征，最早发表的关于IL-23的报道证明，它不仅诱导了STAT3的磷酸化，也诱导了STAT4的磷酸化。众所周知，STAT4还可以调节IL-23受体复合体的一种成分IL-12R？1的表达。综上所述，已发表的发现和我们的初步数据使我们假设，在EAE过程中，IL-23和STAT4在CD4T细胞中以相同的途径发挥作用，并且STAT4管理着CD4T细胞中的致病信号，这是在中枢神经系统炎症过程中赋予脑源性所必需的。为了测试这一点，我们提出了以下具体目标：目标1：确定在中枢神经系统炎症过程中STAT4表达对CD4T细胞功能的影响。目的：探讨中枢神经系统炎症过程中CD4T细胞内源性表达STAT4的必要条件。目的：探讨STAT4信号与IL-23通路在中枢神经系统炎症中的相互作用。总而言之，这些研究旨在提供有关EAE期间中枢神经系统炎症的细胞介质的新信息，并有助于准确定义控制脑源性CD4T细胞发育的属性和分子调节因素。我们的长期目标是阐明STAT4在促进慢性炎症性疾病(如多发性硬化症)中的意义，希望能够确定一个转录靶点，用于未来的治疗干预。

 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.