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

• Published in: Immunity (Cambridge, Mass.) Vol. 56; no. 9; pp. 2021 - 2035.e8
• Main Authors: Luda, Katarzyna M., Longo, Joseph, Kitchen-Goosen, Susan M., Duimstra, Lauren R., Ma, Eric H., Watson, McLane J., Oswald, Brandon M., Fu, Zhen, Madaj, Zachary, Kupai, Ariana, Dickson, Bradley M., DeCamp, Lisa M., Dahabieh, Michael S., Compton, Shelby E., Teis, Robert, Kaymak, Irem, Lau, Kin H., Kelly, Daniel P., Puchalska, Patrycja, Williams, Kelsey S., Krawczyk, Connie M., Lévesque, Dominique, Boisvert, François-Michel, Sheldon, Ryan D., Rothbart, Scott B., Crawford, Peter A., Jones, Russell G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.09.2023
• Subjects: 3-Hydroxybutyric Acid - metabolism; 3-Hydroxybutyric Acid - pharmacology; acetyl-CoA; Acetylation; Animals; cancer immunology; CD8+ T cells; CD8-Positive T-Lymphocytes; effector function; epigenetics; Histones - metabolism; ketolysis; Ketone Bodies; metabolism; Mice; TCA cycle; CD8+ T cells; effector function; ketolysis; TCA cycle; cancer immunology; ketone bodies; metabolism; acetyl-CoA; epigenetics; CD8(+) T cells
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2023.07.002

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.