Histone Lactylation Drives CD8 T Cell Metabolism and Function

Raychaudhuri, D.; Singh, P.; Hennessey, M.; Tannir, A. J.; Chakraborty, B.; Natarajan, S. M.; Goswami, S.

doi:10.1101/2023.08.25.554830

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bioRxiv · 10.1101/2023.08.25.554830

Histone Lactylation Drives CD8 T Cell Metabolism and Function

Raychaudhuri, D.·Singh, P.·Hennessey, M.·Tannir, A. J.·Chakraborty, B.·Natarajan, S. M.·Goswami, S.

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Abstract

The activation and functional differentiation of CD8 T cells are linked to metabolic pathways that result in the production of lactate. Lactylation is a lactate-derived histone post-translational modification (hPTM); 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 phenotype and function. Further, we note distinct impacts of H3K18la and H3K9la on CD8 T cell subsets linked to their specific metabolic profiles. Importantly, we demonstrate that modulation of H3K18la and H3K9la by targeting metabolic and epigenetic pathways regulates CD8 T cell effector function including anti-tumor immunity in preclinical models. Overall, our study uncovers the unique contributions of H3K18la and H3K9la in modulating CD8 T cell phenotype and function intricately associated with metabolic state.

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Raychaudhuri, D., Singh, P., Hennessey, M., Tannir, A. J., Chakraborty, B., Natarajan, S. M., Goswami, S.. 2023-08-27. Histone Lactylation Drives CD8 T Cell Metabolism and Function. https://doi.org/10.1101/2023.08.25.554830

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