Role of splicing factor SRSF1 in T cell function and autoimmunity

系统性红斑狼疮(SLE)是一种原因不明的自身免疫性疾病，主要发病于 女性育龄妇女，影响包括皮肤和关节在内的多个器官，并有并发症 重要器官，如肾脏和大脑。细胞内信号、基因改变引起的T细胞功能障碍 表达和功能被认为是这种疾病的发病机制的核心。申请者使用了 发现并鉴定了一种富含丝氨酸的剪接因子1(SRSF1) 人类T细胞中关键信号基因CD3 Zeta链的调节。此外，申请者还展示了 SRSF1是一种新的IL-2调节因子，是T细胞功能必需的细胞因子。有趣的是，T 几名SLE患者的细胞SRSF1水平降低，其过表达可促进IL-2 制作。这表明SRSF1的异常表达可能导致T细胞功能缺陷和 因此要对疾病的病理生理学进行研究。为了推进这些概念，并确定SRSF1在 整个生物体内的免疫系统，申请人已经培育出缺乏SRSF1基因的小鼠 有条件地在T细胞中。有趣的是，这只小鼠在T细胞表型和功能上有缺陷，包括减少 表达CD3 Zeta链，降低IL-2，增加促炎因子IL-17的产生。这个 老鼠会产生自身抗体，并出现肾脏疾病的症状。有趣的是，雌激素下调SRSF1的表达 健康女性T细胞的表达水平，而男性则不是。根据生成的初步证据， 在T细胞SRSF1缺陷的小鼠中，假设SRSF1是T细胞的关键调节因子 细胞功能及其缺陷促进自身免疫及相关病理的表达。为了测试这一点 假设申请人将-1)确定SRSF1如何控制T细胞动态平衡和功能，并使 自身免疫和相关病理的发展2)决定了SRSF1的T细胞特异性缺失 影响自发性和诱发性自身免疫性疾病以及3)决定SRSF1的作用和调节 在SLE患者和正常人的T细胞中。申请人提议对一部小说进行刻画 这将有助于确定SRSF1在T细胞功能中的作用以及自身免疫和 使用细胞和分子免疫学方法进行相关病理学研究。同时，在人类上提出的研究 T细胞将提供与SLE发病机制中荷尔蒙方面的分子联系。

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown cause, which mainly afflicts women in their childbearing years and affects multiple organs including the skin and joints with complications in vital organs such as kidneys and brain. T cell dysfunction due to altered intracellular signaling, gene expression, and function, is thought to be central in the pathogenesis of this disease. The applicant used a discovery approach and identified a protein namely serine arginine-rich splicing factor 1 (SRSF1) as a regulator of a critical signaling gene - CD3 zeta chain, in human T cells. Furthermore, the applicant showed that SRSF1 is a novel regulator of interleukin (IL)-2, a cytokine necessary for T cell function. Interestingly, T cells from several patients with SLE have reduced levels of SRSF1 and its overexpression improves IL-2 production. This suggests that aberrant SRSF1 expression may contribute to defective T cell function and therefore to disease pathophysiology. To advance these concepts, and to determine the role of SRSF1 in the immune system within a whole organism, the applicant has generated mice lacking the Srsf1 gene conditionally in T cells. Intriguingly, this mouse has defects in T cell phenotype and function, including reduced expression of CD3 zeta chain, reduced IL-2, and increased proinflammatory IL-17 cytokine production. The mouse develops autoantibodies and signs of kidney disease. Interestingly, estrogen downregulates SRSF1 expression levels in T cells from healthy women but not men. Based on the preliminary evidence generated in human T cells and in the T cell Srsf1-deficient mouse, the hypothesis is that SRSF1 is a critical regulator of T cell function and its deficiency promotes the expression of autoimmunity and related pathology. To test this hypothesis the applicant will - 1) Determine how SRSF1 controls T cell homeostasis and function and enables development of autoimmunity and related pathology 2) Determine how T cell-specific deletion of SRSF1 influences spontaneous and induced autoimmune disease and 3) Determine the role and regulation of SRSF1 in T cells from SLE patients and normal subjects. The applicant proposes the characterization of a novel mouse, which will help define the role of SRSF1 in T cell function and the expression of autoimmunity and related pathology using cellular and molecular immunology approaches. In parallel, studies proposed in human T cells will provide a molecular link to hormonal aspects of SLE pathogenesis.