Role of splicing factor SRSF1 in T cell function and autoimmunity

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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.