Ketolysis drives CD8+ T cell effector function through effects on histone acetylation

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. WilliamsConnie M. Krawczyk, Dominique Lévesque, François Michel Boisvert, Ryan D. Sheldon, Scott B. Rothbart, Peter A. Crawford, Russell G. Jones

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2021-2035.e8
JournalImmunity
Volume56
Issue number9
DOIs
StatePublished - Sep 12 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Keywords

  • CD8 T cells
  • TCA cycle
  • acetyl-CoA
  • cancer immunology
  • effector function
  • epigenetics
  • ketolysis
  • ketone bodies
  • metabolism

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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