过氧化物酶体增殖物活化受体γ辅激活因子-1α（PGC-1α）影响记忆性CD8+ T细胞分化的机制研究

The metabolic switch from glycolysis to fatty acid oxidation and oxidative phosphorylation in CD8+ T cells is crucial for their development into long-lived CD8+ memory T cells. But the molecular mechanisms underlying these processes remain unclear. In our previous study, quantitative proteomic analysis of CD8+ memory T cells were performed. It was showed that the expression of more than twenty metabolic enzymes were regulated by PGC-1α in CD8+ memory T cells, which suggest that PGC-1α may act as a metabolic regulator and play an important role in the development of CD8+ memory T cells. In this project, we will evaluate the dynamics of PGC-1α expression and its post-translational modifications during the differentiation of CD8+ memory T cells; investigate the effects of PGC-1α on fatty acid oxidation and oxidative phosphorylation in CD8+ memory T cells and illustrating the exact role of PGC-1α in the development of CD8+ memory T cells. We also will make efforts to expore the upstream regulatory mechanisms of PGC-α activity. This study may provide novel concept and theoretical basis for better immunotherapy as well as vaccination design in the future.

在记忆性CD8+ T细胞分化过程中，细胞能量来源由糖酵解为主转向以脂肪酸氧化和线粒体氧化磷酸化为主。这一代谢重塑过程深刻地影响了记忆性CD8+ T细胞的分化和功能，但其具体分子调节机制仍不完全清楚。在前期研究中，我们对记忆性CD8+ T细胞进行了定量蛋白质组学分析，发现过氧化物酶体增殖物活化受体γ辅激活因子-1α（PGC-1α）影响了二十多个代谢酶的表达，提示其可能作为代谢调节因子在记忆性CD8+ T细胞分化过程中发挥重要作用。本研究将观察PGC-1α在记忆性CD8+ T细胞分化过程中蛋白表达水平和修饰水平的变化，并利用过表达和基因敲降研究PGC-1α在记忆性CD8+ T细胞中对脂肪酸氧化和线粒体氧化磷酸化等代谢通路的调节作用，以及对记忆性CD8+ T细胞分化和功能的影响。我们还将对PGC-1α的上游调节机制进行探索研究。本项目的实施将对免疫治疗和疫苗设计的改进提供新的思路和理论依据。