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 <i>Dot1L</i> in vitro, CD8 T cells retained in vivo proliferative capacity and antitumor reactivity. Moreover, <i>Dot1L</i> 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.
Authors
- Nikolina Bąbała
- Teun van den Brand (ORCID: https://orcid.org/0000-0002-9335-7468)
- Natalie Proost (ORCID: https://orcid.org/0009-0001-3282-793X)
- Bram van den Broek (ORCID: https://orcid.org/0000-0003-1037-907X)
- Tibor van Welsem
- Muddassir Malik (ORCID: https://orcid.org/0000-0002-6273-5956)
- Willem-Jan de Leeuw (ORCID: https://orcid.org/0000-0001-8172-6804)
- Maxime Kempers (ORCID: https://orcid.org/0000-0002-4457-8408)
- Eliza Mari Kwesi‐Maliepaard (ORCID: https://orcid.org/0000-0001-9658-1935)
- Jannie Borst
- Heinz Jacobs (ORCID: https://orcid.org/0000-0001-6227-9850)
- Elselien Frijlink (ORCID: https://orcid.org/0000-0002-9249-8074)
- Liesbeth Hoekman (ORCID: https://orcid.org/0000-0002-3552-6390)
- Fred van Leeuwen (ORCID: https://orcid.org/0000-0002-7267-7251)
- Elzo de Wit (ORCID: https://orcid.org/0000-0003-2883-1415)
- Muhammad Assad Aslam (ORCID: https://orcid.org/0000-0003-1905-2583)
Institutions
- Leiden University Medical Center (NL)
- The Netherlands Cancer Institute (NL)
- Amsterdam Neuroscience (NL)
- Oncode Institute (NL)
- Cancer Genomics Centre (NL)
- Amsterdam University Medical Centers (NL)
- Cancer Center Amsterdam (NL)
- Vrije Universiteit Amsterdam (NL)
- University of Amsterdam (NL)
Publication Details
- Journal
- Science Advances
- Published
- 2025-12-12
- DOI
- https://doi.org/10.1126/sciadv.adw1289
- Citations
- 1
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.81