Ketogenesis-generated β-hydroxybutyrate is an epigenetic regulator of CD8+ T cell memory development

Elucidation of metabolic flux and switch is fundamental for understanding of CD8+ memory T (Tm) cell development. Glycogen, an intracellular carbon reservoir, has long been functionally considered as the use of energy metabolism. However, our recent study indicated that glycogen metabolism, directed by a cytosolic phosphoenolpyruvate carboxykinase (Pck1), controls the formation and maintenance of CD8+ Tm cells through regulating the redox homeostasis1. This unusual metabolic program raises the question of how Pck1 is upregulated in CD8+ Tm cells. Here, we show that mitochondrial acetyl-CoA is shunted to ketogenesis, which indirectly regulates Pck1 expression. Mechanistically, ketogenesis-derived β-hydroxybutyrate (BHB) is stocked in CD8+ Tm cells, which epigenetically modifies H3K9 of FoxO1 and PGC-1α with β-hydroxybutyrylation so to upregulate these genes expression. As a result, FoxO1 and PGC-1α cooperatively upregulates Pck1 expression, thus directing the carbon flow along the gluconeogenic pathway to glycogen and the pentose phosphate pathway. These results unveil that the ketogenesis acts as an unusual metabolic pathway in CD8+ Tm cells, linking epigenetic modification required for memory development. H3K9bhb CHIP-seq done in CD8+ Tm cells treated with BHB