Mitochondrial ATP promotes T cell differentiation through chromatin accessibility.
basic_science · Level V
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- Record sourced from PubMed, PMID 42727574.
- Also identified by DOI 10.1016/j.cell.2026.08.023.
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Abstract
Immune elimination of chronic infection or cancer requires cytotoxic CD8<sup>+</sup> T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process. Here, we report the ability of D-α-hydroxybutyrate (DAHB) to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to oxidative phosphorylation supported by fatty acid oxidation. This conversion elevates the level of a phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induced CD8 effector gene transcription was coupled to bioenergetics by BAF-complex-dependent remodeling of chromatin at effector loci. DAHB-enhanced CD8<sup>+</sup> T cell antitumor activity both in vitro and in vivo. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function.