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Ketolysis drives CD8+ T cell effector function through effects on histone acetylation
Katarzyna M Luda et al. Immunity. 2023.


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.

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

Highlights

•Ketolysis regulates CD8+ T cell metabolism and effector responses in vivo
•Exogenous ketone bodies enhance CD8+ T cell bioenergetics and cytokine production
•The ketone body βOHB is preferred over glucose for synthesis of acetyl-CoA
•βOHB-derived acetyl-CoA regulates histone acetylation at effector gene loci