PDK2通过线粒体代谢调控CD8+效应T细胞分化和功能的机制研究

Although preview studies had demonstrated that mitochondrial oxidation phosphorylation contributed to the formation of CD8+ memory T cell, the exact role of mitochondrial metabolism in differentiation and function of CD8+ effector T cell poorly understood. PDK2 regulates oxidation phosphorylation through controlling pyruvate metabolism in mitochondrial. In our study, we found that the differentiation and function of CD8+ effector T cell is enhanced in Pdk2-/- mouse during LCMV acute infection, but potential molecular mechanism remains unclear. In this study, we choose P14 mouse, which recognize GP33 site of LCMV, to investigate the regulated role of PDK2 in proliferation, effector and metabolism of CD8+ T cell in vivo. Furthermore, we further investigate the ECAR/OCR, mitochondrial copy, ATP production, mitochondrial depolarization, mitoROS production and expression of metabolism genes in CD8+ effector T cell of Pdk2-/- mouse, revealing that the molecular mechanism of PDK2 regulate mitochondrial metabolism of CD8+ effector T cell. These results will clarify the mechanism of PDK2 involved in regulating the process of CD8+ effector T cell differentiation, which provide a new strategy to regulation of adaptive immunity through target PDK2 protein activity.

线粒体氧化磷酸化（OXPHOS）可促进记忆性CD8+T细胞的形成，但是其对效应性CD8+T细胞的功能调节尚未明确。PDK2可抑制线粒体丙酮酸代谢，但其是否可调节效应性CD8+T细胞的功能尚不清楚。前期对急性LCMV病毒感染研究，我们发现PDK2 KO小鼠其效应性CD8+T细胞的数量和功能都显著提高。本研究拟结合ECAR/OCR、线粒体拷贝数、膜电位极化水平及代谢相关基因的表达变化，明确PDK2通过调控OXPHOS 促进效应性CD8+T细胞分化及功能的分子机制。使用P14小鼠建立LCMV病毒感染模型，确证PDK2对效应性CD8+ T细胞分化和效应的调控作用。最后利用PDK2抑制剂，在体证实下调PDK2活性对LCMV病毒感染病理进程的调节结果。本研究将明确PDK2通过调控OXPHOS 影响效应性CD8+T细胞的分化及功能，为慢性病毒感染等疾病的临床治疗提供新策略。