Histone Lactylation Drives CD8 T Cell Metabolism and Function

CD8 T cells undergo metabolic adaptations following activation to support cytotoxic functions against pathogen-infected cells and cancer cells. upregulations of glycolysis, mitochondrial metabolism, and lactate generation mark CD8 T cell activation. Lactylation is a lactate-derived histone post-translational modification, however it's relevance in the context of CD8 T cell activation and function in not known. Here, we show enrichment for H3K18-lactylation (H3K18la) and H3K9-lactylation (H3K9la) in human and murine CD8 T cells, which act as transcription initiators of key genes regulating CD8 T cell-mediated cytotoxicity and effector functions. We demonstrate that exogenous lactate down regulate H3K18la and H3K9la while endogenous metabolic pathways primarily drive H3K18la and H3K9la in CD8 T cells. H3K9la is regulated by both glycolysis and mitochondrial metabolic pathways whereas H3K18la is selectively derived from glycolysis. Additionally, our data underscore the link between H3K18la and mitochondrial fission and the association of H3K9la with mitochondrial fusion which contribute to the specific energy metabolism patterns observed in different T cell states. Importantly, we note distinct impacts of H3K18la and H3K9la on CD8 T cells, while H3K9la plays a critical role in naive, activated as well as memory CD8 T cells, H3K18la acts as a major regulator of gene transcription in activated CD8 T cells. Overall, our data demonstrate that endogenous metabolic pathways drive histone lactylation which subsequently govern mitochondrial dynamics, metabolism and function in CD8 T cells. Further, it uncovers the unique contributions of H3K18la and H3K9la in modulating CD8 T cell phenotype, intricately associated with their metabolic status.