METTL3通过调控LncHOTAIRM1激活CD8+T细胞自噬介导肝移植急性排斥反应

肝移植急性排斥反应严重影响病人长期存活率和生存质量，CD8+T细胞是肝移植急性排斥反应时的关键效应细胞。申请人既往研究证实在肝移植急性排斥反应中自噬可以促进CD8+T细胞增殖活化，介导了急性排斥反应。体外预实验发现：肝移植急性排斥反应时病人外周血CD8+T细胞LncHOTAIRM1表达升高，LncHOTAIRM1可显著增强T细胞自噬，促进其存活和炎症因子分泌。进一步预实验发现m6A甲基化酶METTL3可以通过m6A甲基化修饰LncHOTAIRM1而增强其吸附miR-137，进而上调ATG7促进T细胞自噬活动。据此我们推测：METTL3可以通过m6A甲基化修饰LncHOTAIRM1诱导CD8+T细胞自噬介导肝移植急性排斥反应。本项目拟在前期基础上，从细胞、动物和临床水平验证METTL3通过调控LncHOTAIRM1诱导CD8+T细胞自噬介导肝移植急性排斥反应的机制。

Hepatic acute rejection after liver transplantation seriously affects the long-term survival and life quality of patients, and CD8+T cells are the key effector cells in the hepatic acute rejection. Our previous studies confirmed that autophagy mediated hepatic acute rejection by promoting the proliferation and activation of CD8+T cells in rat liver transplantation model . Our pre-experiment showed that the expression of LncHOTAIRM1 was significantly increased in CD8+T cells of peripheral blood from the liver transplant patients with hepatic acute rejection, LncHOTAIRM1 significantly enhanced the autophagy of T cells and promoted the survival and inflammatory cytokines secretion of T cells in vitro. Further preliminary experiments in vitro showed that METTL3 enhanced the spongy adsorption of LncHOTAIRM1 to miR-137 through m6A methylation, and then promoted the autophagy of T cells by upregulation of ATG7. Therefore, we speculate that METTL3 activates CD8+T autophagy to mediate acute rejection in liver transplantation by m6A methylation of LncHOTAIRM1. On the basis of previous studies, this project further systematically elucidates the mechanism by which METTL3 regulates LncHOTAIRM1 to promote the autophagy of CD8+T cells and mediates hepatic acute rejection in liver transplantation at the cellular, animal and clinical levels.