The Methyltransferase DOT1L Controls Activation and Lineage Integrity in CD4+ T Cells during Infection and Inflammation

Sebastian Scheer, Jessica Runting, Michael Bramhall, Brendan Russ, Aidil Zaini, Jessie Ellemor, Grace Rodrigues, Judy Ng, Colby Zaph

Research output: Contribution to journalArticleResearchpeer-review

Abstract

CD4+ T helper (Th) cell differentiation is controlled by lineage-specific expression of transcription factors and effector proteins, as well as silencing of lineage-promiscuous genes. Lysine methyltransferases (KMTs) comprise a major class of epigenetic enzymes that are emerging as important regulators of Th cell biology. Here, we show that the KMT DOT1L regulates Th cell function and lineage integrity. DOT1L-dependent dimethylation of lysine 79 of histone H3 (H3K79me2) is associated with lineage-specific gene expression. However, DOT1L-deficient Th cells overproduce IFN-γ under lineage-specific and lineage-promiscuous conditions. Consistent with the increased IFN-γ response, mice with a T-cell-specific deletion of DOT1L are susceptible to infection with the helminth parasite Trichuris muris and are resistant to the development of allergic lung inflammation. These results identify a central role for DOT1L in Th2 cell lineage commitment and stability and suggest that inhibition of DOT1L may provide a therapeutic strategy to limit type 2 immune responses.

Original languageEnglish
Article number108505
Number of pages19
JournalCell Reports
Volume33
Issue number11
DOIs
Publication statusPublished - 15 Dec 2020

Keywords

  • asthma
  • CD4 T cells
  • DOT1L
  • IFN-γ
  • Th1
  • Th2
  • Trichuris muris

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