A novel immune-regulatory role of TRAIL in T cell activation and autoimmune inflammation via an apoptosis-independent pathway

• Main Authors: I-Tsu Chyuan, 全以祖
• Other Authors: 許秉寧
• Format: Others
• Language: en_US
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/465tcy

博士 === 國立臺灣大學 === 臨床醫學研究所 === 106 === 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, suggesting an immune-regulatory role of TRAIL besides triggering apoptosis in immune-mediated diseases. However, the immune-regulatory role of TRAIL in regulating autoimmune responses in autoimmune diseases is still not clear. In our study, we created an animal model of inflammatory arthritis and demonstrated that TRAIL significantly inhibited joint inflammation and reduced the severity of arthritis. The suppression of joint inflammation was not due to the TRAIL-mediated induction of apoptosis in T cells, macrophages or synovial fibroblasts. In contrast, TRAIL directly inhibited activated T cell proliferation and suppressed the production of cytokines, which indicated that TRAIL exerted its anti-inflammatory effects by direct inhibition of T-cell activation. Moreover, TRAIL-R knockout (TRAIL-R KO) mice developed more severe disease, and the protective effects of TRAIL were abolished in the experimental arthritis model in TRAIL-R KO mice. From these results, we conclude that TRAIL suppresses joint inflammation via an apoptosis-independent pathway and directly inhibits T cell activation. To further address the immune-regulatory role and molecular mechanism of TRAIL in regulating T cell activation in autoimmune diseases, we used experimental autoimmune encephalomyelitis (EAE) animal model. The results have demonstrated that TRAIL suppressed autoimmune encephalomyelitis and inhibited T cell reactivity to neuro-antigen [myelin oligodendrocyte glycoprotein (MOG)35-55] in murine EAE, and the effects were dependent on TRAIL-R signaling. Moreover, TRAIL directly inhibited activation of MOG35-55-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. These results indicate that TRAIL/TRAIL-R interaction regulates CD4 T cell activation in autoimmune inflammation and directly suppresses T cell activation via inhibiting TCR signaling, suggesting that TRAIL-R serves as a novel immune checkpoint in T cell responses. Our results provide a novel apoptosis-independent, immune regulatory role for TRAIL in suppressing autoimmune inflammation and shed light on the development of effective new therapies for autoimmune diseases.