Zhu Kaixiang, Rohila Deepak, Zhao Yuanling, Shytikov Dmytro, Wu Lize, Zhao Fan, Hu Shurong, Xu Qin, Jin Xuexiao, Lu Linrong
Department of Cardiology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China.
Research (Wash D C). 2025 Jan 2;8:0545. doi: 10.34133/research.0545. eCollection 2025.
Protein phosphatase 2A (PP2A) is one of the most abundant serine/threonine phosphatases and plays critical roles in regulating cell fate and function. We previously showed that PP2A regulates the differentiation of CD4 T cells and the development of thymocytes. Nevertheless, its role in CD8 T cells remains elusive. By ablating the catalytic subunit α (Cα) of PP2A in CD8 T cells, we revealed the essential role of PP2A in promoting the effector functions of CD8 T cells. Notably, PP2A Cα-deficient CD8 T cells exhibit reduced proliferation and decreased cytokine production upon stimulation in vitro. In vivo, mice lacking PP2A Cα in T cells displayed defective immune responses against lymphocytic choriomeningitis virus infection, associated with reduced CD8 T cell expansion and decreased cytokine production. Consistently, the ablation of the PP2A Cα subunit in CD8 T cells results in attenuated antitumor activity in mice. There is a notable decrease in the infiltration of PP2A Cα-deficient CD8 T cells within the tumor microenvironment, and the cells that do infiltrate exhibit diminished effector functions. Mechanistically, PP2A Cα deficiency impedes CD28-induced AKT Ser phosphorylation, thus impairing CD8 T cell costimulation signal. Collectively, our findings underscore the critical role of phosphatase PP2A as a propeller for CD28-mediated costimulation signaling in CD8 T cell effector function by fine-tuning T cell activation.
蛋白磷酸酶2A（PP2A）是最丰富的丝氨酸/苏氨酸磷酸酶之一，在调节细胞命运和功能方面发挥着关键作用。我们之前表明，PP2A调节CD4 T细胞的分化和胸腺细胞的发育。然而，其在CD8 T细胞中的作用仍不清楚。通过在CD8 T细胞中敲除PP2A的催化亚基α（Cα），我们揭示了PP2A在促进CD8 T细胞效应功能中的重要作用。值得注意的是，PP2A Cα缺陷的CD8 T细胞在体外刺激后增殖减少，细胞因子产生降低。在体内，T细胞中缺乏PP2A Cα的小鼠对淋巴细胞性脉络丛脑膜炎病毒感染表现出有缺陷的免疫反应，这与CD8 T细胞扩增减少和细胞因子产生降低有关。一致地，在CD8 T细胞中敲除PP2A Cα亚基会导致小鼠抗肿瘤活性减弱。在肿瘤微环境中，PP2A Cα缺陷的CD8 T细胞浸润明显减少，并且浸润的细胞表现出减弱的效应功能。从机制上讲，PP2A Cα缺陷会阻碍CD28诱导的AKT丝氨酸磷酸化，从而损害CD8 T细胞共刺激信号。总的来说，我们的研究结果强调了磷酸酶PP2A通过微调T细胞激活，作为CD28介导的共刺激信号在CD8 T细胞效应功能中的推进器的关键作用。
