CD8⁺ memory T (Tm) cells are fundamental for protective immunity against infections and cancers ^1-5 . Metabolic activities are crucial in controlling memory T-cell homeostasis, but mechanisms linking metabolic signals to memory formation and survival remain elusive. Here we show that CD8⁺ Tm cells markedly upregulate cytosolic phosphoenolpyruvate carboxykinase (Pck1), the hub molecule regulating glycolysis, tricarboxylic acid cycle and gluconeogenesis, to increase glycogenesis via gluconeogenesis. The resultant glycogen is then channelled to glycogenolysis to generate glucose-6-phosphate and the subsequent pentose phosphate pathway (PPP) that generates abundant NADPH, ensuring high levels of reduced glutathione in Tm cells. Abrogation of Pck1-glycogen-PPP decreases GSH/GSSG ratios and increases levels of reactive oxygen species (ROS), leading to impairment of CD8⁺ Tm formation and maintenance. Importantly, this metabolic regulatory mechanism could be readily translated into more efficient T-cell immunotherapy in mouse tumour models.

中文翻译：

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Pck1指导的糖原代谢程序可调节记忆CD8 + T细胞的形成和维持。

CD8 ⁺记忆T（Tm）细胞对于抵抗感染和癌症^1-5的保护性免疫至关重要。代谢活动在控制记忆T细胞动态平衡中至关重要，但是将代谢信号与记忆形成和生存联系起来的机制仍然难以捉摸。在这里，我们显示CD8 ⁺Tm细胞显着上调胞质磷酸烯醇丙酮酸羧化激酶（Pck1），这是调节糖酵解，三羧酸循环和糖异生的枢纽分子，可通过糖异生增加糖异生。然后，将生成的糖原引导至糖原分解过程以生成6-磷酸葡萄糖，随后的戊糖磷酸途径（PPP）则产生大量NADPH，从而确保Tm细胞中高水平的还原型谷胱甘肽。Pck1-糖原-PPP的废除降低了GSH / GSSG比率，并增加了活性氧（ROS）的水平，导致CD8 ⁺ Tm形成和维持受到损害。重要的是，这种代谢调节机制可以很容易地转化为小鼠肿瘤模型中更有效的T细胞免疫疗法。