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 cancers1,2,3,4,5. 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.

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Fig. 1: Pck1 and Fbp1 were upregulated in CD8+ Tm cells.
Fig. 2: Glycogen metabolism regulates the formation of CD8+ Tm cells.
Fig. 3: Pck1-generated PEP flows to glycogen and PPP.
Fig. 4: PPP is essential for CD8+ Tm homeostasis.
Fig. 5: The Pck1-directed metabolic program regulates CD8 T-cell antitumour immunity.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81788104, 81661128007, 81530080), the National Basic Research Program of China (2014CB542103), the National Natural Science Fund for Young Scholars of China (81502415) and the CAMS Initiative for Innovative Medicine (2016-I2M-1-007).

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B.H. conceived the project, R.M., T.J., H.Z., W.D., X.Ch., P.X., D.C., X.L., X.Y., Y.L., J.M., K.T., Y.Z. (Wuhan), Y.P. and J.L. performed the experiments. R.M., T.J., H.Z. and B.H. analysed the data. R.M., H.Z., X.Ca., X.Q., Y.Z. (Zhengzhou), Y.W. and B.H. contributed to manuscript preparation, and R.M. and B.H. wrote the manuscript.

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Correspondence to Bo Huang.

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Ma, R., Ji, T., Zhang, H. et al. A Pck1-directed glycogen metabolic program regulates formation and maintenance of memory CD8+ T cells. Nat Cell Biol 20, 21–27 (2018). https://doi.org/10.1038/s41556-017-0002-2

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