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Acetate Promotes T Cell Effector Function during Glucose Restriction

MPS-Authors

Qiu,  Jing
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Villa,  Matteo
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Sanin,  Pena David Estaban
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Buck,  Michael D.
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

O’Sullivan,  David
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Ching,  Reagan W.
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Matsushita,  Mai
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Grzes,  Katarzyna
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Jonathan,  D. Curtis
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Kyle,  Ryan L.
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Bakker,  Nikki Van Teijlingen
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Corrado,  Mauro
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Haessler,  Fabian
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Edwards-Hicks,  Joy
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Klein-Geltink,  Ramon
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Jenuwein,  Thomas
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Pearce,  Edward Jonathen
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Pearce,  Erika Laine
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Qiu, J., Villa, M., Sanin, P. D. E., Buck, M. D., O’Sullivan, D., Ching, R. W., et al. (2019). Acetate Promotes T Cell Effector Function during Glucose Restriction. Cell Reports, 27, 2063-2074. doi:10.1016/j.celrep.2019.04.022.


Cite as: http://hdl.handle.net/21.11116/0000-0005-1E6B-3
Abstract
Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is therefore key for maintaining appropriate cell function. For instance, cancer cells use acetate as a substrate alternative to glucose to fuel metabolism and growth. Here, we show that acetate rescues effector function in glucose-restricted CD8+ T cells. Mechanistically, acetate promotes histone acetylation and chromatin accessibility and enhances IFN-γ gene transcription and cytokine production in an acetyl-CoA synthetase (ACSS)-dependent manner. Ex vivo acetate treatment increases IFN-γ production by exhausted T cells, whereas reducing ACSS expression in T cells impairs IFN-γ production by tumor-infiltrating lymphocytes and tumor clearance. Thus, hyporesponsive T cells can be epigenetically remodeled and reactivated by acetate, suggesting that pathways regulating the use of substrates alternative to glucose could be therapeutically targeted to promote T cell function during cancer.