Committee on Molecular Pathology and Molecular Medicine, Chicago, IL, United States.
Department of Medicine, Section of Pulmonary and Critical Care Medicine, Chicago, IL, United States.
Front Immunol. 2018 Nov 1;9:2521. doi: 10.3389/fimmu.2018.02521. eCollection 2018.
Fas (CD95/APO-1) and its ligand (FasL/CD95L) promote the resolution of type 2 lung inflammation and eosinophilia. We previously found that Fas-deficiency on T cells, but not eosinophils, delayed resolution of inflammation. However, Fas can signal both cell death and have a positive signaling function that can actually activate cells. In this study, we investigated whether Fas-induced death or Fas-activated signaling pathways promote resolution of allergic lung inflammation. By increasing T cell survival through two Fas-independent pathways, using Bim-deficient T cells or Bcl-x overexpressing T cells, no differences in resolution of Th2-mediated inflammation was observed. Furthermore, Th2 cells were inherently resistant to Fas-mediated apoptosis and preferentially signaled through non-apoptotic pathways following FasL treatment. Utilizing Fas-mutant mice deficient in apoptotic but sufficient for non-apoptotic Fas signaling pathways, we demonstrate that non-apoptotic Fas signaling in T cells drives resolution of Th2-mediated airway inflammation. Our findings reveal a previously unknown role for non-apoptotic Fas signaling on Th2 cells in the induction of resolution of type 2 inflammation.
Fas（CD95/APO-1）及其配体（FasL/CD95L）可促进 2 型肺部炎症和嗜酸性粒细胞增多症的消退。我们之前发现，T 细胞而非嗜酸性粒细胞上 Fas 的缺失会延迟炎症消退。然而，Fas 既能诱导细胞死亡，又能发挥正向信号作用，实际上能激活细胞。在这项研究中，我们研究了 Fas 诱导的细胞死亡或 Fas 激活的信号通路是否能促进过敏性肺部炎症的消退。通过两条 Fas 非依赖性途径增加 T 细胞的存活率，使用 Bim 缺陷型 T 细胞或 Bcl-x 过表达 T 细胞，我们观察到 Th2 介导的炎症消退没有差异。此外，Th2 细胞固有地对 Fas 介导的细胞凋亡具有抗性，并且在 FasL 处理后优先通过非凋亡信号通路发出信号。利用 Fas 突变型小鼠，这些小鼠缺乏凋亡但 Fas 信号通路的非凋亡成分充足，我们证明了 T 细胞中非凋亡 Fas 信号转导驱动 Th2 介导的气道炎症消退。我们的研究结果揭示了 Th2 细胞中非凋亡 Fas 信号转导在诱导 2 型炎症消退中的一个先前未知的作用。
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