Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan.
College of Medicine, Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.
Front Immunol. 2018 Jan 22;9:15. doi: 10.3389/fimmu.2018.00015. eCollection 2018.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals after interacting with its receptor (TRAIL-R). Although the actual biological role of TRAIL remains to be elucidated, recent accumulating evidence implies that TRAIL regulates immune responses and immune cell homeostasis an apoptosis-independent pathway, suggesting a novel immune-regulatory role of TRAIL in autoimmune diseases. The purpose of this study is to address the immune-regulatory role and molecular mechanism of TRAIL in regulating T cell activation in autoimmune diseases.
TRAIL was administered to mice to induce experimental autoimmune encephalomyelitis (EAE), and to evaluate its impact on neuroinflammation and disease activity. The effects of TRAIL on neuroantigen [myelin oligodendrocyte glycoprotein (MOG)]-activated T cell proliferation and cytokine production were investigated. TRAIL-treated MOG-activated splenic Th17 cells were further adoptively transferred into Rag1 KO mice to induce passive EAE. Gene expression profiles of CD4 T cells from EAE mice treated with TRAIL were analyzed by RNA sequencing and transcriptome analysis.
TRAIL suppressed autoimmune encephalomyelitis and inhibited T cell reactivity to neuro-antigen in murine EAE, and the effects were dependent on TRAIL-R signaling. Moreover, TRAIL directly inhibited activation of MOG-activated CD4 T cells, resulting in suppression of neuroinflammation and reduced disease activity in adoptive transfer-induced EAE. Furthermore, TRAIL-R signaling inhibited phosphorylation of proximal T cell receptor (TCR)-associated tyrosine kinases in activated CD4 T cells. Importantly, TRAIL/TRAIL-R interaction downregulated TCR downstream signaling genes in RNA sequencing and transcriptome analysis.
TRAIL/TRAIL-R interaction regulates CD4 T cell activation in autoimmune inflammation and directly suppresses T cell activation inhibiting TCR signaling, suggesting that TRAIL-R serves as a novel immune checkpoint in T cell responses.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）与受体（TRAIL-R）相互作用后传递凋亡信号，诱导细胞凋亡。尽管 TRAIL 的实际生物学作用仍有待阐明，但最近越来越多的证据表明，TRAIL 通过一种非凋亡途径调节免疫反应和免疫细胞稳态，提示 TRAIL 在自身免疫性疾病中具有新的免疫调节作用。本研究旨在探讨 TRAIL 在自身免疫性疾病中调节 T 细胞激活的免疫调节作用及其分子机制。
用 TRAIL 处理小鼠诱导实验性自身免疫性脑脊髓炎（EAE），评估其对神经炎症和疾病活动的影响。研究了 TRAIL 对神经抗原[髓鞘少突胶质糖蛋白（MOG）]激活的 T 细胞增殖和细胞因子产生的影响。将 TRAIL 处理的 MOG 激活的脾 Th17 细胞过继转移到 Rag1 KO 小鼠中诱导被动 EAE。通过 RNA 测序和转录组分析分析 TRAIL 处理的 EAE 小鼠 CD4 T 细胞的基因表达谱。
TRAIL 抑制实验性自身免疫性脑脊髓炎和抑制小鼠 EAE 中 T 细胞对神经抗原的反应，其作用依赖于 TRAIL-R 信号。此外，TRAIL 直接抑制 MOG 激活的 CD4 T 细胞的激活，导致过继转移诱导的 EAE 中神经炎症的抑制和疾病活动的减少。此外，TRAIL-R 信号抑制激活的 CD4 T 细胞中近端 T 细胞受体（TCR）相关酪氨酸激酶的磷酸化。重要的是，TRAIL/TRAIL-R 相互作用下调 RNA 测序和转录组分析中的 TCR 下游信号基因。
TRAIL/TRAIL-R 相互作用调节自身免疫炎症中的 CD4 T 细胞激活，并直接抑制 T 细胞激活，抑制 TCR 信号，提示 TRAIL-R 作为 T 细胞反应中的新型免疫检查点。
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