A Pck1-directed glycogen metabolic program regulates formation and maintenance of memory CD8+ T cells

Abstract

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.