Acetate Promotes T Cell Effector Function during Glucose Restriction

Qui, Jing; Mateo, Villa; Sanin, David E.; Buck, Michael D.; O'Sullivan, David; Ching, Reagen; Matsushita, Mai; Grzes, Katarzyna; Winkler, Frances; Chang, Chih-Hao; Curtis, Jonathen; Kyle, Ryan; B, Nikki Van Teijlingen; Corrado, Mauro; Haessler, Fabian; Alfei, Francesca; Edwards-Hicks, Joy; Maggi Jr., Leonard B.; Zehn, Dietmar; Egawa, Takeshi; Bengsch, Bertram; Klein-Geltink, Ramon; Jenuwein, Thomas; Pearce, Edward J.; Pearce, Erika L.

doi:10.1016/j.celrep.2019.04.022

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Acetate Promotes T Cell Effector Function during Glucose Restriction

MPS-Authors

Qui, Jing
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons201434

Mateo, Villa
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Sanin, David E.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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

/persons/resource/persons201374

O'Sullivan, David
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons204357

Ching, Reagen
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons204382

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

/persons/resource/persons204377

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

Curtis, Jonathen
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Kyle, Ryan
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

B, Nikki Van Teijlingen
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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

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

Alfei, Francesca
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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

/persons/resource/persons201360

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

/persons/resource/persons191130

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

/persons/resource/persons201435

Pearce, Edward J.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons201431

Pearce, Erika L.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Qui, J., Mateo, V., Sanin, D. E., Buck, M. D., O'Sullivan, D., Ching, R., 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: https://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.