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

Immunity. 2023 Sep 12;56(9):2021-2035.e8. doi: 10.1016/j.immuni.2023.07.002. Epub 2023 Jul 28.


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.

Keywords: CD8(+) T cells; TCA cycle; acetyl-CoA; cancer immunology; effector function; epigenetics; ketolysis; ketone bodies; metabolism.

Publication types

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

MeSH terms

  • 3-Hydroxybutyric Acid / metabolism
  • 3-Hydroxybutyric Acid / pharmacology
  • Acetylation
  • Animals
  • CD8-Positive T-Lymphocytes*
  • Histones* / metabolism
  • Ketone Bodies
  • Mice


  • 3-Hydroxybutyric Acid
  • Histones
  • Ketone Bodies