Journal Article

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

Tang, Ke, Dong, Wenqian, Ma, Jingwei, Chen, Xinfeng, Zhang, Huafeng, Yin, Xiaonan, Zhang, Yi, Qin, Xiaofeng, Xu, Pingwei, Liang, Xiaoyu, Wan, Yonghong, Peng, Yue’e, Huang, Bo, Ji, Tiantian, Lu, Jinzhi, Ma, Ruihua, Chen, Degao, Liu, Yuying, Cao, Xuetao

2018

Overview

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. Glycogen metabolism controls memory T cells. Ma et al. show that the metabolic gene PCK1 promotes glycogen formation, which is used in the pentose phosphate pathway, generating glutathione that is important for counteraction of ROS and thus promotion of memory T-cell maintenance, and resulting in improved antitumour immunity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 3-Mercaptopropionic Acid - pharmacology / 631/67/2327 / 631/67/327 / 692/699/67 / Adoptive Transfer / Animal models / Animals / Biomedical and Life Sciences / Cancer Research / CD8 antigen / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / CD8-Positive T-Lymphocytes - transplantation / Cell Biology / Citric Acid Cycle - drug effects / Citric Acid Cycle - genetics / Citric Acid Cycle - immunology / Developmental Biology / Enzyme Inhibitors - pharmacology / Female / Gene Expression Regulation, Neoplastic / Gluconeogenesis / Gluconeogenesis - drug effects / Gluconeogenesis - genetics / Gluconeogenesis - immunology / Glucose - immunology / Glucose - metabolism / Glutathione / Glycogen / Glycogen - immunology / Glycogen - metabolism / Glycolysis / Glycolysis - drug effects / Glycolysis - genetics / Glycolysis - immunology / Homeostasis / Homeostasis - immunology / Immunity / Immunologic Memory / Immunological memory / Immunotherapy / Intracellular Signaling Peptides and Proteins - antagonists & inhibitors / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - immunology / Letter / Life Sciences / Lymphocytes / Lymphocytes T / Melanoma, Experimental - drug therapy / Melanoma, Experimental - genetics / Melanoma, Experimental - immunology / Melanoma, Experimental - metabolism / Memory cells / Metabolism / Mice / Mice, Inbred C57BL / Mice, Transgenic / NADP / NADP - immunology / NADP - metabolism / Pentose / Pentose phosphate pathway / Pentose Phosphate Pathway - drug effects / Pentose Phosphate Pathway - genetics / Pentose Phosphate Pathway - immunology / Phosphoenolpyruvate Carboxykinase (GTP) - antagonists & inhibitors / Phosphoenolpyruvate Carboxykinase (GTP) - genetics / Phosphoenolpyruvate Carboxykinase (GTP) - immunology / Reactive oxygen species / Reactive Oxygen Species - immunology / Reactive Oxygen Species - metabolism / Regulatory mechanisms (biology) / Skin Neoplasms - drug therapy / Skin Neoplasms - genetics / Skin Neoplasms - immunology / Skin Neoplasms - metabolism / Stem Cells / Tricarboxylic acid cycle / Tumors