Autoimmune rheumatologic diseases
Lymphopenia is one of the most common clinical features in patients with systemic lupus erythematosus (SLE), and associates with severe disease and comorbidities, yet the underlying mechanisms remain unclear. By discovery approaches we previously identified the serine arginine-rich splicing factor 1 (SRSF1) binding to the 3`UTR of CD3 zeta in human T cells, and showed the role of SRSF1 in T cell function. We showed that SRSF1 levels are decreased in T cells from patients with SLE, and associate with severe disease. Because SRSF1 is an essential pro-survival factor and controls the expression of Bcl-2-related anti-apoptotic genes, we hypothesized that SRSF1 controls T cell homeostasis and its deficiency may contribute to lymphopenia. To this end, we generated T cell-conditional Srsf1-deficient mice. We observed a peripheral T cell lymphopenia in these mice, with increased apoptosis of T cells ex vivo, and after Fas crosslinking. Transcriptomics profiling of effector CD4 T cells from Srsf1-cko mice revealed aberrant expression of apoptosis-related genes. We confirmed the decreased expression of the anti-apoptotic long (L) isoform of Bcl-x (Bcl-xL) in T cells from Srsf1-deficient mice. Of clinical relevance is our finding that lower expression of SRSF1 correlated with low levels of Bcl-xL in T cells and with lymphopenia in SLE patients. Importantly, overexpression of Srsf1 in T cells from patients with SLE, improved cell survival. These results suggest that SRSF1 controls T cell homeostasis via Bcl-xL in patients with SLE, and reduced SRSF1 expression is an underlying molecular defect which contributes to lymphopenia in SLE.