Background/Purpose: T cells from patients with systemic lupus erythematosus (SLE) express reduced amounts of the critical CD3 zeta signaling chain, and produce low levels of the vital cytokine interleukin (IL)-2. 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 generation of a full-length CD3 zeta transcript over a short spliced unstable isoform to promote normal expression of CD3 zeta chain in human T cells. We found that SRSF1 expression levels are decreased in SLE T cells, more so in patients with worse disease. We further showed that force expression of SRSF1 into SLE T cells rescues IL-2 production. While these findings suggest that SRSF1 deficiency is important in SLE T cell dysfunction, it remains unknown whether SRSF1 contributes to immune-mediated disease. To this end, in this study, we generated mice with a T cell-restricted deletion of SRSF1 to evaluate the mechanistic role of SRSF1 in T cell dysfunction and the development of immune-mediated disease in vivo.

Methods: Srsf1 “floxed” mice were crossed with Lck.Cre (distal promoter) transgenic mice to delete SRSF1 specifically in mature T cells and generate the T cell Srsf1 conditional knockout (Srsf1-cko) mice. Mice were euthanized at 10-16 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, enzyme-linked immunosorbent assay (ELISA) and intracellular staining. Serum and urine were collected at monthly intervals to assess autoantibody levels and proteinuria respectively. Non-lymphoid (lung, liver, kidney) tissues were fixed, sectioned and stained with hematoxylin and eosin to evaluate histopathology.

Results: Srsf1-cko mice develop peripheral T cell lymphopenia, with a striking reduction in the CD8 compartment. 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 increased levels of 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. These results indicate that lack of SRSF1 leads to an aberrant T cell homeostasis, aberrant T cell activation, with increased inflammatory cytokine production, autoantibody development and kidney damage.

Conclusion: SRSF1 is a novel regulator of T cell homeostasis and 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-factor-in-t-cell-homeostasis-and-its-selective-loss-in-t-cells-causes-autoimmunity-and-lupus-like-nephritis/