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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 β-hydroxybutyrate (βOHB) 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 βOHB directly increases CD8⁺ Teff cell IFN-γ 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 βOHB 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.

Ketone bodies promote CD8⁺ T cell metabolism and effector function through regulation of epigenetic programming