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

Glycogen has long been considered to have a function in energy metabolism. However, our recent study indicated that glycogen metabolism, directed by cytosolic phosphoenolpyruvate carboxykinase Pck1, controls the formation and maintenance of CD8(+) memory T (T-mem) cells by regulating redox homeostasis(1). This unusual metabolic program raises the question of how Pck1 is upregulated in CD8(+) T-mem cells. Here, we show that mitochondrial acetyl coenzyme A is diverted to the ketogenesis pathway, which indirectly regulates Pck1 expression. Mechanistically, ketogenesis-derived beta-hydroxybutyrate is present in CD8(+) T-mem cells; beta-hydroxybutyrate epigenetically modifies Lys 9 of histone H3 (H3K9) of Foxo1 and Ppargc1a (which encodes PGC-1 alpha) with beta-hydroxybutyrylation, upregulating the expression of these genes. As a result, FoxO1 and PGC-1 alpha cooperatively upregulate Pck1 expression, therefore directing the carbon flow along the gluconeogenic pathway to glycogen and the pentose phosphate pathway. These results reveal that ketogenesis acts as an unusual metabolic pathway in CD8(+) T-mem cells, linking epigenetic modification required for memory development. Zhang et al. show that ketogenesis-derived beta-hydroxybutyrate (BHB) epigenetically modifies H3K9 of Foxo1 and Ppargc1a to regulate Pck1, which in turn controls metabolic flux and CD8(+) memory T-cell development.