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
Affiliations
Sebastian Scheer
Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia; Corresponding author
Jessica Runting
Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia
Michael Bramhall
Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia
Brendan Russ
Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia; Department of Microbiology, Monash University, Clayton VIC 3800, Australia
Aidil Zaini
Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia
Jessie Ellemor
Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia
Grace Rodrigues
Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia
Judy Ng
Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia
Colby Zaph
Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia; Corresponding author
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.
