Background/Purpose:

T cells from patients with systemic lupus erythematosus (SLE) exhibit defects in signaling including a reduced expression of the CD3 zeta signaling chain, and defects in cytokine production such as decreased IL-2 production. We used a discovery approach namely mass spectrometry analysis of proteins “pulled-down” by a CD3 zeta mRNA-defined oligonucleotide, and identified the splicing regulator serine arginine-rich splicing factor 1 (SRSF1). We showed that SRSF1 promotes normal expression of CD3 zeta chain, and upregulates IL-2 production in human T cells. We found that SRSF1 expression levels are decreased in SLE T cells, and associates with worse disease. Force expression of SRSF1 into SLE T cells rescued IL-2 production. These results suggest that SRSF1 deficiency is important in the SLE T cell dysfunction. However, it is unknown how SRSF1 deficiency contributes to immune-mediated disease. To this end, we have generated mice with a T cell-restricted deletion of SRSF1, and our goal is to evaluate the mechanistic role of SRSF1 in T cell dysfunction and the development of immune-mediated disease in vivo.

Methods:

T cell Srsf1 conditional knockout (Srsf1-cko) mice were generated by crossing Srsf1-flox mice with d.Lck.Cre (distal promoter) transgenic mice to delete SRSF1 in mature T cells. Mice were euthanized at 10-20 weeks of age, or aged to >1 year. Central (thymus) and peripheral (spleen, lymph nodes) lymphoid organs were analyzed for immune cell phenotype and function by flow cytometry. Serum and urine were collected to assess autoantibody levels and proteinuria respectively. Kidney tissues were fixed, sectioned and stained with hematoxylin and eosin to evaluate histopathology. To assess regulatory T cells (Treg) function in vivo, adoptive transfer of Tregs followed by induction of colitis in two models – dextran sodium sulfate (DSS)-induced colitis in B6 mice, and the naïve CD4 transfer-induced colitis in RAG-ko mice, were utilized.

Results:

Srsf1-cko mice develop peripheral T cell lymphopenia at younger ages, whereas aged mice exhibit lymphocytosis and lymphoproliferation. CD4 T cells exhibit an activated phenotype and produce increased amounts of IFN-γ and IL-17 but lower amounts of IL-2 upon ex vivo stimulation. The Srsf1-cko mice develop autoantibodies, and exhibit increased proteinuria compared to control mice. Kidney histopathology shows evidence of glomerular damage with glomerular hyperproliferation, glomerular capillary hyperplasia, and interstitial infiltration of mononuclear cells. Tregs from Srsf1-cko mice are dysfunctional and are unable to suppress colitis in vivo. These results indicate that a lack of SRSF1 selectively in T cells, leads to impaired T cell function with reduced IL-2 production, increased inflammatory cytokine production, and aberrant Treg function, resulting in autoantibody development and tissue damage.

Conclusion: SRSF1 is a novel regulator of T cell function, and its deficiency leads to autoimmunity and lupus-like nephritis. Therefore, deficiency of SRSF1 in T cells may represent a molecular defect that contributes to the pathogenesis of systemic autoimmune disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/serinearginine-rich-splicing-factor-1-srsf1-is-a-novel-regulator-of-t-cell-function-and-its-selective-deficiency-in-t-lymphocytes-leads-to-autoimmunity-and-lupus-like-nephritis/