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

• Published in: Immunity (Cambridge, Mass.) Vol. 48; no. 3; pp. 556 - 569.e7
• Main Authors: Meyer zu Horste, Gerd, Przybylski, Dariusz, Schramm, Markus A., Wang, Chao, Schnell, Alexandra, Lee, Youjin, Sobel, Raymond, Regev, Aviv, Kuchroo, Vijay K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.03.2018; Elsevier Limited
• Subjects: Antigens; Apoptosis; Autoimmunity; CD95; Cell differentiation; Clonal deletion; Computer applications; Cytokines; death receptor; Differentiation (biology); EAE; Fas; Gene expression; Helper cells; Interleukin 17; Interleukin 6; Ligands; Lymphocytes; Lymphocytes T; Mutation; Nervous system; Nuclear transport; Sequestering; Stability; STAT1; Stat1 protein; STAT3; Stat3 protein; T cell receptors; Th1 cells; Th17 cells; Transcription factors; Translocation; Tumor necrosis factor-TNF; CD95; Th1 cells; autoimmunity; STAT1; STAT3; EAE; Fas; apoptosis; Th17 cells; death receptor
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2018.03.008

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. •Fas promotes the in vivo pathogenicity of T helper 17 cells•Fas promotes the stability of T helper 17 cells by preventing STAT1 activation•Fas regulates the STAT1 versus STAT3 balance by binding and sequestering STAT1•Fas is a cell-intrinsic regulator of competing T helper cell differentiation programs 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.