The splicing factor SF2/ASF is a novel regulator of IL-2 transcription and rescues IL-2 production in T lymphocytes from patients with SLE (P6288)

Abstract

Abstract Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, which afflicts mainly women in the childbearing years, and causes painful arthritis, skin disease and complications in the kidneys and brain. Abnormal T lymphocytes in SLE not only regulate autoantibody-producing B cells, but also are responsible for target organ infiltration. T cells from patients with SLE express decreased levels of the T cell receptor (TCR) - associated CD3 zeta (ζ) chain, a feature directly linked to their poor interleukin (IL)-2 production. We recently showed that the splicing regulator splicing factor 2 / alternative splicing factor (SF2/ASF) enhances the expression of CD3ζ chain by limiting the production of an unstable mRNA splice variant. Here we show that SF2/ASF expression levels are decreased in T cells from SLE patients, more so in patients with higher SLE disease activity index (SLEDAI). Importantly, we show that overexpression of SF2/ASF in SLE T cells restores IL-2 production. In parallel, silencing SF2/ASF expression in normal T cells reduces their IL-2 secretion. Finally we show that SF2/ASF induces transcriptional activity of the IL-2 promoter and that SF2/ASF is recruited to the IL-2 promoter indicating its role in IL-2 transcription. These results identify SF2/ASF as a novel regulator of IL-2 expression in human T cells and a potential molecular mechanism underlying the T cell defect in SLE.