NAD-蛋白去乙酰化酶Sirtuin1通路调控CD8 T细胞记忆及耗竭分化的机制研究

CD8 T细胞记忆形成和功能耗竭在代谢及表观遗传学层次受到严格调控。NAD是细胞能量代谢的重要调控因子，对维持线粒体活性及氧化还原稳态至关重要。NAD依赖的蛋白去乙酰化酶Sirtuin1（SIRT1）参与CD4 T细胞分化。但NAD-SIRT1在CD8 T细胞记忆形成及耗竭中作用未知。我们近期研究发现：记忆CD8 T细胞呈现高水平NAD，NAD处理促进T细胞记忆表型形成及增强线粒体备用呼吸能力等代谢特征。我们通过构建的CD8 T细胞特异SIRT1敲除小鼠证明，SIRT1参与调控CD8 T细胞记忆形成及耗竭。本项目将在此工作基础上，联合李斯特菌急性感染模型及小鼠肿瘤模型，系统研究NAD-SIRT1在CD8 T细胞效应/记忆分化及耗竭过程中的作用。应用组学、基因编辑、生化等技术深入探讨相关的线粒体代谢及表观遗传学调控机制。本研究将对提高CD8 T细胞抗感染及肿瘤提供重要理论依据。

Both CD8 T cell memory formation and exhaustion are tightly controlled at the metabolic and epigenetic level. NAD is a co-factor of many key enzymes of cellular metabolism and important regulator of mitochondrial activity and redox reactions. Sirtuin1(SIRT1) is NAD dependent protein deacetylase and regulates CD4 T cell differentiation. However, it remains unclear whether and how does NAD-SIRT1 signaling axis regulate CD8 T cell exhaustion and memory formation. Interestingly, our preliminary data suggest that memory CD8 T cells harbor higher cellular NAD and lower surface CD38 expression as compared to effector cells. Boosting cellular NAD during CD8 T cell priming promotes memory phenotype and enhanced mitochondrial spare respiratory capacity, which is the cardinal feature of memory T cell metabolism. Furthermore, with CD8 T cell specific SIRT1 KO mice, we show that SIRT1 is critically involved in CD8 T cell differentiation and functional exhaustion. In the present study, with the listeria-OVA infection model and mouse melanoma model, we aim to understand the role of NAD and SIRT1 in CD8 T cell effector, memory or exhaustion and uncover the metabolic or epigenetic basis for this regulation. Our study will provide important evidence for improving CD8 T cell immunity against infections and cancer.