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. [Display omitted] •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 Environmental nutrient availability influences T cell function, yet the substrates that fuel T cell metabolism in vivo are poorly defined. Here, Luda and Longo et al. identify ketolysis (breakdown of ketone bodies) as a metabolic pathway required for optimal CD8+ T cell effector function in vivo. Ketone bodies, including βOHB, are physiologic fuels for T cells, preferred over glucose for acetyl-CoA synthesis, and regulate effector function through effects on histone acetylation.