Histone methyltransferase DOT1L maintains cell state and restricts cytotoxic potential of CD8 T cells

The histone methyltransferase DOT1L is emerging as a central epigenetic regulator in immune cells. Loss of DOT1L during development of CD8 T cells in vivo leads to gain of memory characteristics but has also been reported to compromise CD8 T cell viability and antitumor reactivity. Here, we determined the cell-intrinsic role of DOT1L in mature mouse CD8 T cells. After conditional deletion of Dot1L in vitro, CD8 T cells retained in vivo proliferative capacity and antitumor reactivity. Moreover, Dot1L knockout CD8 T cells showed increased antigen-specific cytotoxicity toward tumor cells in vitro. Mechanistically, loss of DOT1L resulted in an altered cell state with loss of T cell and gain of innate-like features. These transcriptional changes were mediated by loss of DOT1L methyltransferase activity in a dose-dependent manner. Our findings show that in mature CD8 T cells, ablation of DOT1L activity is well tolerated and reprograms them to gain innate-like memory cell characteristics and enhance intrinsic cytotoxic capacity.