Fas Promotes T Helper 17 Cell Differentiation and Inhibits T Helper 1 Cell Development by Binding and Sequestering Transcription Factor STAT1

Publication date: 20 March 2018
Source:Immunity, Volume 48, Issue 3
Author(s): Gerd Meyer zu Horste, Dariusz Przybylski, Markus A. Schramm, Chao Wang, Alexandra Schnell, Youjin Lee, Raymond Sobel, Aviv Regev, Vijay K. Kuchroo
The death receptor Fas removes activated lymphocytes through apoptosis. Previous transcriptional profiling predicted that Fas positively regulates interleukin-17 (IL-17)-producing T helper 17 (Th17) cells. Here, we 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 were impaired. Fas-deficient Th17 cells instead developed a Th1-cell-like transcriptional profile, which a new algorithm predicted to depend on STAT1. Experimentally, Fas indeed bound and sequestered STAT1, and Fas deficiency enhanced IL-6-induced STAT1 activation and nuclear translocation, whereas deficiency of STAT1 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 opposing STAT1 and STAT3 to have a direct impact on autoimmunity.

Teaser

Fas is a well-known death receptor that can also mediate non-apoptotic functions. Meyer zu Horste et al. demonstrate that Fas promotes the stability and pathogenicity of T helper 17 cells by sequestering and inhibiting the activation of STAT1 and regulating the availability of opposing STAT1 and STAT3.


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