Cytotoxic T cell differentiation is guided by epigenome adaptations, but how epigenetic mechanisms control lymphocyte development has not been well defined. Here we show that the histone methyltransferase DOT1L, which marks the nucleosome core on active genes, safeguards normal differentiation of CD8⁺ T cells. T cell-specific ablation of Dot1L resulted in loss of naïve CD8⁺ T cells and premature differentiation toward a memory-like state, independent of antigen exposure and in a cell-intrinsic manner. Mechanistically, DOT1L controlled CD8⁺ T cell differentiation by ensuring normal T cell receptor density and signaling. DOT1L also maintained epigenetic identity, in part by indirectly supporting the repression of developmentally regulated genes. Finally, deletion of Dot1L in T cells resulted in an impaired immune response. Through our study, DOT1L is emerging as a central player in physiology of CD8⁺ T cells, acting as a barrier to prevent premature differentiation and controlling epigenetic integrity.

细胞毒性T细胞的分化受表观基因组适应性的指导，但是表观遗传机制如何控制淋巴细胞的发育尚不清楚。在这里，我们显示了组蛋白甲基转移酶DOT1L，它标记了活性基因上的核小体核心，可以保护CD8 ⁺ T细胞的正常分化。Dot1L的T细胞特异性消融导致幼稚的CD8 ⁺ T细胞丢失，并朝着记忆样状态过早分化，而与抗原暴露无关，并且以细胞内在方式进行。从机械上讲，DOT1L控制CD8 ⁺通过确保正常的T细胞受体密度和信号传导来实现T细胞分化。DOT1L还保持了表观遗传特性，部分是通过间接支持对发育调控基因的抑制。最后，T细胞中Dot1L的缺失导致免疫反应受损。通过我们的研究，DOT1L逐渐成为CD8 ⁺ T细胞生理学的核心参与者，可作为防止过早分化和控制表观遗传完整性的障碍。