GSE111244
Fas promotes T helper-17 cell differentiation and inhibits development of T helper-1 cells by binding and sequestering the STAT1 transcription factor
The death receptor Fas removes activated lymphocytes through apoptosis. Previous  transcriptional profiling predicted that Fas positively regulates interleukin (IL)-17-producing T helper (Th17) cells. We here demonstrate that Fas promoted the generation and stability of Th17 cells and prevented their differentiation into Th1 cells. Mice with T cell- and Th17 cell-specific deletion of Fas were protected from induced autoimmunity and Th17 cell differentiation and stability was impaired. Fas deficient Th17 cells instead developed a Th1 cell-like transcriptional profile, which we predicted by a new algorithm to depend on STAT1. Experimentally, Fas indeed bound and sequestered STAT1 and Fas deficiency enhanced IL-6 induced STAT1 activation and nuclear translocation, whereas Fas-STAT1 double-deficiency reversed the transcriptional changes induced by Fas deficiency. Thus, our computational and experimental approach identified Fas as a regulator of the Th17-to-Th1 cell balance by controlling the availability of the opposing STAT1 and STAT3 proteins with direct impact on autoimmunity. Overall design: comparative RNA-seq study comparing the expression of C57BL/6 wildtype vs. Fas-deficient (lpr) sorted naive CD4+ T cells differentiated without cytokines (Th0 cells) or with TGF-ß1 with IL-6 (Th17 cells)