Ketolysis drives CD8+ T cell effector function through effects on histone acetylation
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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.
Original language | English |
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Journal | Immunity |
Volume | 56 |
Issue number | 9 |
Pages (from-to) | 2021-2035.e8 |
Number of pages | 24 |
ISSN | 1074-7613 |
DOIs | |
Publication status | Published - 2023 |
Bibliographical note
Publisher Copyright:
© 2023 The Authors
- acetyl-CoA, cancer immunology, CD8 T cells, effector function, epigenetics, ketolysis, ketone bodies, metabolism, TCA cycle
Research areas
ID: 366763950