氧化磷酸化调控双阴T细胞免疫抑制功能影响非酒精性脂肪性肝炎发病的机制研究

双阴性T细胞（Double negative T cells, DNT）在维持肝脏免疫稳态中起重要作用。我们前期发现，在NASH中肝内DNT细胞能量代谢改变、免疫抑制功能下调，而过继转移正常DNT可抑制非酒精性脂肪性肝炎（NASH）的炎症反应及发病进程。但NASH中，DNT细胞能量代谢的改变及功能异常的原因和相关性未知。本课题从调控DNT细胞能量代谢的角度探讨对其免疫抑制功能的影响。首先，系统地研究正常与NASH小鼠肝内DNT糖酵解、氧化磷酸化等能量代谢表型的变化；其次，进一步探讨NASH肝内代谢微环境改变影响DNT氧化磷酸化下调的主要机制；接下来又深入研究了NASH肝内DNT氧化磷酸化下调通过H3K9/K27ac-Tbet/Eomes-PRF1/GZMB途径影响其抑制功能的可能作用机制；最后我们又在临床病人PBMC及病理标本中验证了上述发现，以期待为NASH的防治提供新的免疫干预靶点。

Double negative T (DNT) cells play an important role in maintaining immune homeostasis of the liver. Our previous studies discovered that adoptive transfer of DNT could inhibit the progression of non-alcoholic steatohepatitis (NASH). However, the immunosuppressive function of DNT cells in the liver was significantly down-regulated in NASH, and its specific mechanism remained unclear. In the present study, the effect of DNT cells on its immunosuppressive function was explored from the perspective of regulating their energy metabolism. Firstly, the changes in energy metabolism phenotypes such as glycolysis and oxidative phosphorylation of DNT cells in the livers of the normal mice and the mice with NASH were compared. Secondly, the main mechanism of the effects of the metabolic microenvironment changes in the liver of NASH on the down-regulation of the oxidative phosphorylation of the DNT cells was further investigated; and then this study probed into the mechanism of the effect of the down-regulation of oxidative phosphorylation of the DNT cells in the liver of NASH on the immunosuppressive function through H3K9/K27ac-Tbet/Eomes-PRF1/GZMB pathway. Finally, we verified the above findings in clinical patients with PBMC and pathological specimens. This study will provide a new experimental basis for the prevention and treatment of NASH by means of immune intervention.