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

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  • 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
  • And 7 others
  • Connie M. Krawczyk
  • Dominique Lévesque
  • François Michel Boisvert
  • Ryan D. Sheldon
  • Scott B. Rothbart
  • Peter A. Crawford
  • Russell G. Jones

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
JournalImmunity
Volume56
Issue number9
Pages (from-to)2021-2035.e8
Number of pages24
ISSN1074-7613
DOIs
Publication statusPublished - 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors

    Research areas

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

ID: 366763950