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Ketolysis is a metabolic driver of CD8+ T cell effector function through histone acetylation

ABSTRACT: Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. However, the metabolic pathways critical for optimal T cell responses remain poorly understood. Here, we identify ketone bodies (KBs) – including -hydroxybutyrate (OHB) and acetoacetate (AcAc) – as essential fuels supporting CD8+ T cell metabolism and effector function. Ketolysis is an intrinsic feature of highly functional CD8+ T effector (Teff) cells and OHB directly increases CD8+ Teff cell IFN- production and cytolytic activity. Using metabolic tracers, we establish that CD8+ Teff cells preferentially use KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boost the respiratory capacity of CD8+ T cells and TCA cycle-dependent metabolic pathways that fuel T cell growth. Mechanistically, we find that OHB is a major substrate for acetyl-CoA production in CD8+ T cells and regulates 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.

INSTRUMENT(S): autoflex

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Cell Culture

DISEASE(S): Acute Leukemia

SUBMITTER: Dominique Levesque

LAB HEAD: Russel G Jones

PROVIDER: PXD036292 | Pride | 2023-10-11

REPOSITORIES: Pride

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