Ketolysis Drives CD8 T cell Effector Function Through Effects on Histone Acetylation

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2023 Jul 29

PMID 37516105

Authors

Katarzyna M Luda

Joseph Longo

Susan M Kitchen-Goosen

Lauren R Duimstra

Eric H Ma

McLane J Watson

Brandon M Oswald

Zhen Fu

Zachary Madaj

Ariana Kupai

Bradley M Dickson

Lisa M DeCamp

Michael S Dahabieh

Shelby E Compton

Robert Teis

Irem Kaymak

Kin H Lau

Daniel P Kelly

Patrycja Puchalska

Kelsey S Williams

Connie M Krawczyk

Dominique Levesque

Francois-Michel Boisvert

Ryan D Sheldon

Scott B Rothbart

Peter A Crawford

Russell G Jones

Affiliations

Soon will be listed here.

Abstract

Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)-as essential fuels supporting CD8 T cell metabolism and effector function. βOHB directly increased CD8 T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8 Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8 T cell function. Mechanistically, βOHB was a major substrate for acetyl-CoA production in CD8 T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8 T cell effector responses.

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References

Horton J, Davidson M, Kurishima C, Vega R, Powers J, Matsuura T . The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI Insight. 2019; 4(4). PMC: 6478419. DOI: 10.1172/jci.insight.124079. View

Cox P, Kirk T, Ashmore T, Willerton K, Evans R, Smith A . Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metab. 2016; 24(2):256-68. DOI: 10.1016/j.cmet.2016.07.010. View

Karagiannis F, Peukert K, Surace L, Michla M, Nikolka F, Fox M . Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19. Nature. 2022; 609(7928):801-807. PMC: 9428867. DOI: 10.1038/s41586-022-05128-8. View

Lercher A, Bhattacharya A, Popa A, Caldera M, Schlapansky M, Baazim H . Type I Interferon Signaling Disrupts the Hepatic Urea Cycle and Alters Systemic Metabolism to Suppress T Cell Function. Immunity. 2019; 51(6):1074-1087.e9. PMC: 6926485. DOI: 10.1016/j.immuni.2019.10.014. View

Vander Heiden M, Lunt S, Dayton T, Fiske B, Israelsen W, Mattaini K . Metabolic pathway alterations that support cell proliferation. Cold Spring Harb Symp Quant Biol. 2012; 76:325-34. DOI: 10.1101/sqb.2012.76.010900. View

Northrop J, Thomas R, Wells A, Shen H . Epigenetic remodeling of the IL-2 and IFN-gamma loci in memory CD8 T cells is influenced by CD4 T cells. J Immunol. 2006; 177(2):1062-9. DOI: 10.4049/jimmunol.177.2.1062. View

Sugimoto M, Ikeda S, Niigata K, Tomita M, Sato H, Soga T . MMMDB: Mouse Multiple Tissue Metabolome Database. Nucleic Acids Res. 2011; 40(Database issue):D809-14. PMC: 3245187. DOI: 10.1093/nar/gkr1170. View

Durinck S, Spellman P, Birney E, Huber W . Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt. Nat Protoc. 2009; 4(8):1184-91. PMC: 3159387. DOI: 10.1038/nprot.2009.97. View

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z . clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2(3):100141. PMC: 8454663. DOI: 10.1016/j.xinn.2021.100141. View

10.

Ruan H, Crawford P . Ketone bodies as epigenetic modifiers. Curr Opin Clin Nutr Metab Care. 2018; 21(4):260-266. DOI: 10.1097/MCO.0000000000000475. View

11.

Cahill Jr G . Fuel metabolism in starvation. Annu Rev Nutr. 2006; 26:1-22. DOI: 10.1146/annurev.nutr.26.061505.111258. View

12.

Martin M, Condotta S, Harty J, Badovinac V . Population dynamics of naive and memory CD8 T cell responses after antigen stimulations in vivo. J Immunol. 2011; 188(3):1255-65. PMC: 3262935. DOI: 10.4049/jimmunol.1101579. View

13.

Rohrig F, Schulze A . The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer. 2016; 16(11):732-749. DOI: 10.1038/nrc.2016.89. View

14.

Best J, Blair D, Knell J, Yang E, Mayya V, Doedens A . Transcriptional insights into the CD8(+) T cell response to infection and memory T cell formation. Nat Immunol. 2013; 14(4):404-12. PMC: 3689652. DOI: 10.1038/ni.2536. View

15.

Shimazu T, Hirschey M, Newman J, He W, Shirakawa K, Le Moan N . Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 2012; 339(6116):211-4. PMC: 3735349. DOI: 10.1126/science.1227166. View

16.

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

17.

Wilhelm C, Surendar J, Karagiannis F . Enemy or ally? Fasting as an essential regulator of immune responses. Trends Immunol. 2021; 42(5):389-400. DOI: 10.1016/j.it.2021.03.007. View

18.

Lien E, Westermark A, Zhang Y, Yuan C, Li Z, Lau A . Low glycaemic diets alter lipid metabolism to influence tumour growth. Nature. 2021; 599(7884):302-307. PMC: 8628459. DOI: 10.1038/s41586-021-04049-2. View

19.

Wei R, Zhou Y, Li C, Rychahou P, Zhang S, Titlow W . Ketogenesis Attenuates KLF5-Dependent Production of CXCL12 to Overcome the Immunosuppressive Tumor Microenvironment in Colorectal Cancer. Cancer Res. 2022; 82(8):1575-1588. PMC: 9018557. DOI: 10.1158/0008-5472.CAN-21-2778. View

20.

Xie Z, Zhang D, Chung D, Tang Z, Huang H, Dai L . Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation. Mol Cell. 2016; 62(2):194-206. PMC: 5540445. DOI: 10.1016/j.molcel.2016.03.036. View