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; 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 mouse CD8⁺ T cells, which act as transcription initiators of key genes regulating CD8⁺ T cell function. Further, we note distinct patterns of H3K18la and H3K9la in CD8⁺ T cell subsets linked to their specific metabolic profiles. Additionally, we find that modulation of H3K18la and H3K9la by targeting metabolic and epigenetic pathways influence CD8⁺ T cell effector function, including antitumor immunity, in preclinical models. Overall, our study uncovers the potential roles of H3K18la and H3K9la in CD8⁺ T cells.

CD8⁺ T 细胞的激活和功能分化与导致乳酸产生的代谢途径有关。乳酸化是一种乳酸衍生的组蛋白翻译后修饰;然而，组蛋白乳酸化与 CD8⁺ T 细胞活化和功能的相关性尚不清楚。在这里，我们展示了人和小鼠 CD8⁺ T 细胞中 H3K18 乳酰化 （H3K18la） 和 H3K9 乳酸化 （H3K9la） 的富集，它们作为调节 CD8⁺ T 细胞功能的关键基因的转录起始因子。此外，我们注意到 CD8⁺ T 细胞亚群中 H3K18la 和 H3K9la 的不同模式与其特异性代谢特征相关。此外，我们发现在临床前模型中，通过靶向代谢和表观遗传途径调节 H3K18la 和 H3K9la 会影响 CD8⁺ T 细胞效应器功能，包括抗肿瘤免疫。总体而言，我们的研究揭示了 H3K18la 和 H3K9la 在 CD8⁺ T 细胞中的潜在作用。