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. Up regulation of glycolysis, mitochondrial metabolism, and lactate generation mark CD8 T cell activation. Lactylation is a newly identified lactate-derived histone post-translational modification (hPTMs), however, the relevance of histone lactylation in the context of CD8 T cell activation and function is not known. Here, we show the enrichment of 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 function. Further, we delineate the distinct functional 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 in activated CD8 T cells. H3K9la is driven by both glycolysis and mitochondrial metabolic pathways whereas H3K18la is selectively derived from glycolysis, perpetuating a feed-forward loop. Of note, exogenous lactate does not regulate H3K18la or H3K9la in CD8 T cells, rather it reduces the enrichment of these marks in the promoter and enhancer regions of genes. Additionally, we demonstrate 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. The distinct involvement of H3K18la and H3K9la in shaping mitochondrial dynamics highlights their role as potential epigenetic regulators of T cell metabolism. Overall, our data uncovers the crucial function of histone lactylation in governing the transcriptomic landscape regulating CD8 T cell function. Furthermore, it sheds light on the unique contributions of H3K18la and H3K9la in modulating CD8 T cell phenotype, intricately associated with their metabolic status. ### Competing Interest Statement The authors have declared no competing interest.