Category: Autoimmune rheumatologic diseases
T cells from patients with systemic lupus erythematosus (SLE) exhibit a hyperactive phenotype with aberrant cytokine production. By discovery approaches we previously identified the serine arginine-rich splicing factor 1 (SRSF1) to bind to the CD3 zeta mRNA in human T cells. We showed that SRSF1 levels are decreased in T cells upon stimulation. Importantly SRSF1 expression levels are decreased in T cells from patients with SLE, and associate with worse disease. To define the role of SRSF1 in T cell physiology and in autoimmune disease, we generated Srsf1-T cell-conditional knockout (Srsf1-cko) mice. These mice develop systemic autoimmune disease with elevated serum autoantibodies and lupus nephritis. CD4 T cells from Srsf1-cko mice exhibit an activated/effector phenotype with increased frequencies of aberrant (IL-17, IFN-γ, IL-4) cytokine producing cells upon ex vivostimulation and an elevated T cell activation gene signature. Mechanistically, we found increased activity of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and decreased expression of its inhibitor PTEN. Rapamycin suppressed proinflammatory cytokine production from Srsf1-deficient T cells. Of direct clinical relevance is our finding that in T cells from SLE patients,the expression levels of PTEN were decreased along with SRSF1, and the overexpression of Srsf1 rescued PTEN, and suppressed mTORC1 activity and proinflammatory cytokine production. Our results reveal that SRSF1 is a novel negative regulator of T cell activation and its deficiency in T cells from SLE patients contributes to the pathogenesis of disease.
Takayuki Katsuyama– Postdoctoral fellow, Beth Israel Deaconess Medical Center, Harvard Medical School
Hao Li– Postdoctoral Research fellow, Beth Israel Deaconess Medical Center, Harvard Medical School
Denis Comte– Beth Israel Deaconess Medical Center, Harvard Medical School
George Tsokos– Professor, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School
Vaishali Moulton– Assistant Professor, Beth Israel Deaconess Medical Center, Harvard Medical School