Inhibition of Autophagy Prolongs Recipient Survival Through Promoting CD8+ T Cell Apoptosis in a Rat Liver Transplantation Model
Inhibition of Autophagy Prolongs Recipient Survival Through Promoting CD8+ T Cell Apoptosis in a Rat Liver Transplantation Model
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在大鼠肝移植模型中抑制自噬可通过促进 CD8( ) T 细胞凋亡来延长受体的生存
DOI：
10.3389/fimmu.2019.01356
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发表时间：
2019-06-14
影响因子：
7.3
通讯作者：
Wang, Genshu
中科院分区：
文献类型：
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作者：
Chen, Xiaolong;Wang, Li;Wang, Genshu
在肝移植（LT）中，尽管各种免疫抑制剂已被用于临床实践，急性排斥反应仍然是一种常见的并发症，显着缩短受体的生存。近年来，操纵免疫耐受已被认为是有前途的解决排斥反应的方法之一。自噬是一种进化上保守的蛋白质降解系统，已被报道参与免疫排斥反应，并可能成为建立免疫耐受的靶点。然而，自噬在LT后急性排斥反应中的作用尚未阐明。在这里，我们发现在移植排斥反应患者中，CD 8（+）T细胞的自噬强烈增强，并且自噬水平与排斥反应的严重程度呈正相关。在大鼠急性肝排斥模型中观察到类似的结果。此外，给予自噬抑制剂3-甲基腺嘌呤（3-MA）通过抑制自噬大大降低了CD 8（+）T细胞的活力和功能，这显著延长了大鼠移植物的存活时间。此外，抑制体外活化的CD 8（+）T细胞的自噬可以显著抑制线粒体介导的存活和下调T细胞功能。结论：我们首次发现，抑制自噬可以通过促进CD 8（+）T细胞的凋亡来显著提高肝移植物的存活率，这可能为免疫耐受诱导提供一种新的策略。
In liver transplantation (LT), although various immunosuppressants have been used in clinical practice, acute rejection remains a common complication that significantly shortens recipient survival. In recent years, manipulating immune tolerance has been regarded as one of the promising solutions to rejection. Autophagy, an evolutionarily conserved protein degradation system, has been reported to be involved in immune rejection and may be a target to establish immune tolerance. However, the role of autophagy in acute rejection reaction after LT has not been elucidated. Here, we showed that the autophagy of CD8(+) T cells was strongly enhanced in patients with graft rejection and that the autophagy level was positively correlated with the severity of rejection. Similar findings were observed in a rat acute hepatic rejection model. Furthermore, administration of the autophagy inhibitor 3-methyladenine (3-MA) largely decreased the viability and function of CD8(+) T cells through inhibiting autophagy, which significantly prolonged graft survival in rats. In addition, inhibiting the autophagy of activated CD8(+) T cells in vitro considerably suppressed mitochondria mediated survival and downregulated T cell function.Conclusions: We first showed that the inhibition of autophagy significantly prolongs liver allograft survival by promoting the apoptosis of CD8(+ )T cells, which may provide a novel strategy for immune tolerance induction.