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

Cell Reports

Michael Bramhall¹  Jessica Runting²  Grace Rodrigues²  Aidil Zaini²  Colby Zaph³  Jessie Ellemor⁴  Judy Ng⁴  Sebastian Scheer⁴  Brendan Russ⁴ 

[1] Corresponding author;Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia;Department of Microbiology, Monash University, Clayton VIC 3800, Australia;Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia;

关键词: DOT1L;    CD4 T cells;    Th1;    Th2;    IFN-γ;    Trichuris muris;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: 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.

【 授权许可】

Unknown