Nutrient-driven histone code determines exhausted CD8 + T cell fates.

Autor: Ma S; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA., Dahabieh MS; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Mann TH; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA., Zhao S; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA., McDonald B; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA., Song WS; Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA., Chung HK; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Farsakoglu Y; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA., Garcia-Rivera L; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA., Hoffmann FA; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA., Xu S; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA., Du VY; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA., Chen D; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA., Furgiuele J; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA., LaPorta M; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA., Jacobs E; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA., DeCamp LM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Oswald BM; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Sheldon RD; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA., Ellis AE; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA.; Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA., Liu L; Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA., He P; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA., Wang Y; Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA., Jang C; Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA., Jones RG; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Kaech SM; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2024 Dec 12, pp. eadj3020. Date of Electronic Publication: 2024 Dec 12.
DOI: 10.1126/science.adj3020
Abstrakt: 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 downregulating 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.
Databáze: MEDLINE