| First Author | Malik M | Year | 2025 |
| Journal | Sci Adv | Volume | 11 |
| Issue | 50 | Pages | eadw1289 |
| PubMed ID | 41385642 | Mgi Jnum | J:376710 |
| Mgi Id | MGI:8271832 | Doi | 10.1126/sciadv.adw1289 |
| Citation | Malik M, et al. (2025) Histone methyltransferase DOT1L maintains cell state and restricts cytotoxic potential of CD8 T cells. Sci Adv 11(50):eadw1289 |
| abstractText | 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. |
