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

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.
Competing Interests: Declaration of interests R.G.J. is a scientific advisor for Agios Pharmaceuticals and Servier Pharmaceuticals and is a member of the Scientific Advisory Board of Immunomet Therapeutics.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)