Alternative splicing of FOXP3 controls regulatory T cell function and Th17 differentiation (P4118)

Abstract

Abstract Eukaryotic cells diversify gene function through alternative splicing, i.e. differential assembly of exons to create distinct protein isoforms. Alternative splicing is common for human FOXP3, the key transcription factor of regulatory T (Treg) cells that is indispensable for maintaining immunological tolerance. Previous studies have demonstrated that Treg cells can exclude exon 7 of FOXP3, which encodes for a leucine zipper region that sustains the Treg cell phenotype. Here we demonstrate that patients suffering from Crohn’s disease (CD) have elevated levels of FOXP3 lacking exon 7, which correlates with disease severity. Moreover, by modulating the pattern of alternative splicing towards exclusion of FOXP3's seventh exon we were able to generate interleukin-2 (IL-2) producing Treg cells. FOXP3 is transiently expressed during Th17 differentiation and we found that exclusion of FOXP3's seventh exon promoted Th17 differentiation. Finally, we demonstrate that expression of FOXP3 lacking exon 7 correlates with increased expression of IL-17 in CD patients. In summary, alternative splicing of FOXP3 regulates both the regulatory T cell phenotype and Th17 differentiation.