Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Department of Neurology, University Hospital Münster, Münster, Germany.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Immunity. 2018 Mar 20;48(3):556-569.e7. 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.
死亡受体 Fas 通过细胞凋亡清除激活的淋巴细胞。先前的转录谱分析预测 Fas 正向调节白细胞介素-17（IL-17）产生的辅助性 T 细胞 17（Th17）细胞。在这里，我们证明 Fas 促进了 Th17 细胞的生成和稳定性，并防止其向 Th1 细胞分化。T 细胞和 Th17 细胞特异性 Fas 缺失的小鼠对诱导性自身免疫具有保护作用，Th17 细胞分化和稳定性受损。Fas 缺陷的 Th17 细胞则表现出 Th1 样细胞的转录特征，一种新的算法预测其依赖于 STAT1。实验表明，Fas 确实与 STAT1 结合并隔离 STAT1，Fas 缺失增强了 IL-6 诱导的 STAT1 激活和核转位，而 STAT1 的缺失则逆转了 Fas 缺失引起的转录变化。因此，我们的计算和实验方法通过控制对立的 STAT1 和 STAT3 的可用性来识别 Fas 作为 Th17 向 Th1 细胞平衡的调节剂，从而对自身免疫产生直接影响。
