The Splicing Factor ASF/SF2 enhances Interleukin-2 production in human T lymphocytes (121.5)

Abstract

Abstract Systemic lupus erythematosus (SLE) is a complex autoimmune disease which afflicts mainly women in the reproductive 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 are also responsible for target organ infiltration. Currently, no specific therapeutic strategies target T cell defects. Moreover, there are no known molecular markers to predict disease activity. Aberrant molecular mechanisms responsible for SLE T cell defects are thus promising targets for therapy, as well as potential biomarkers for disease. 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 alternative splicing factor/ splicing factor 2 (ASF/SF2) enhances the expression of CD3ζ chain by limiting the production of an unstable mRNA splice variant. Here, we show that ASF/SF2 expression levels are decreased in T cells from SLE patients, and correlate with CD3ζ chain expression. Moreover, ASF/SF2 expression correlates inversely with SLE disease activity index (SLEDAI). Further, replenishment of ASF/SF2 in SLE T cells restores IL2 production. These results identify ASF/SF2 as a novel regulator of IL2 expression in human T cells and a potential molecular mechanism underlying the altered T cell defect in SLE.