期刊
IMMUNITY
卷 48, 期 3, 页码 556-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2018.03.008
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类别
资金
- Deutsche Forschungsgemeinschaft (DFG) [ME4050/1-1]
- National Multiple Sclerosis Society postdoctoral fellowship [FG20118-A-1]
- DFG [SCHR 1481/1-1]
- Klarman Cell Observatory at the Broad Institute
- Howard Hughes Medical Institute
- NIH [RO1 NS30843, P01 AI0562999, P01 NS076410, P01 AI039671, P01 AI045757, P01 AI073748]
The death receptor Fas removes activated lymphocytes through apoptosis. Previous transcriptional profiling predicted that Fas positively regulates inter-leukin-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.
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