Nutrient-driven histone code determines exhausted CD8 <sup>+</sup> T cell fates

Shixin Ma(Salk Institute for Biological Studies), Michael S. Dahabieh(Van Andel Institute), Thomas H. Mann(Salk Institute for Biological Studies), Steven Zhao(Salk Institute for Biological Studies), Bryan McDonald(Salk Institute for Biological Studies), Won‐Suk Song(University of California, Irvine), H. Kay Chung(University of North Carolina at Chapel Hill), Yagmur Farsakoglu(Salk Institute for Biological Studies), Lizmarie Garcia-Rivera(Salk Institute for Biological Studies), Filipe Araujo Hoffmann(Salk Institute for Biological Studies), Shihao Xu(Salk Institute for Biological Studies), Victor Y. Du(Salk Institute for Biological Studies), Dan Chen(Salk Institute for Biological Studies), Jesse Furgiuele(Salk Institute for Biological Studies), Michael A. LaPorta(Salk Institute for Biological Studies), Emily Jacobs(Salk Institute for Biological Studies), Lisa M. DeCamp(Van Andel Institute), Brandon M. Oswald(Van Andel Institute), Ryan D. Sheldon(Van Andel Institute), Abigail E. Ellis(Van Andel Institute), Longwei Liu(University of Southern California), Peixiang He(University of California San Diego), Yingxiao Wang(University of Southern California), Cholsoon Jang(University of California, Irvine), Russell G. Jones(Van Andel Institute), Susan M. Kaech(Salk Institute for Biological Studies)
Science
December 12, 2024
10.1126/science.adj3020
Cited by 74Open Access
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Abstract

Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing their protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. We showed that TEX cells shifted from acetate to citrate metabolism by down-regulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. This metabolic switch increased citrate-dependent histone acetylation, mediated by histone acetyltransferase KAT2A-ACLY interactions, at TEX signature genes while reducing acetate-dependent histone acetylation, dependent on p300-ACSS2 complexes, at effector and memory T cell genes. Nuclear ACSS2 overexpression or ACLY inhibition prevented TEX differentiation and enhanced tumor-specific T cell responses. These findings unveiled a nutrient-instructed histone code governing CD8 + T cell differentiation, with implications for metabolic- and epigenetic-based T cell therapies.

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