Histone methyltransferase DOT1L maintains identity 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-features but has also been reported to compromise CD8 T cell viability and activity. 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 anti-tumor reactivity. Moreover, Dot1L knock-out CD8 T cells showed increased antigen-specific cytotoxicity towards tumor cells in vitro. Mechanistically, loss of DOT1L resulted in an altered cell-identity program with loss of T-cell and gain of NK-cell features. These transcriptional changes were mediated by loss of DOT1L methyltransferase activity in a dose-dependent manner. Our findings show that ablation of DOT1L activity in mature CD8 T cells is well-tolerated and rewires their cell identity towards the NK-cell lineage, concomitantly enhancing intrinsic cytotoxic capacity.