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Mucosal Immunol. 2018 Sep;11(5):1524-1536. doi: 10.1038/s41385-018-0052-1. Epub 2018 Jul 23.

Notch ligand Delta-like 4 induces epigenetic regulation of Treg cell differentiation and function in viral infection.

Author information

1
Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
2
Molecular and Cellular Pathology Program, University of Michigan, Ann Arbor, MI, 48109, USA.
3
Department of Cancer Immunology, Genentech, South San Francisco, CA, 94080, USA.
4
Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
5
Department of Cell and Developmental Biology, Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
6
Department of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
7
Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA. nlukacs@umich.edu.
8
Molecular and Cellular Pathology Program, University of Michigan, Ann Arbor, MI, 48109, USA. nlukacs@umich.edu.

Abstract

Notch ligand Delta-like ligand 4 (DLL4) has been shown to regulate CD4 T-cell differentiation, including regulatory T cells (Treg). Epigenetic alterations, which include histone modifications, are critical in cell differentiation decisions. Recent genome-wide studies demonstrated that Treg have increased trimethylation on histone H3 at lysine 4 (H3K4me3) around the Treg master transcription factor, Foxp3 loci. Here we report that DLL4 dynamically increased H3K4 methylation around the Foxp3 locus that was dependent upon upregulated SET and MYDN domain containing protein 3 (SMYD3). DLL4 promoted Smyd3 through the canonical Notch pathway in iTreg differentiation. DLL4 inhibition during pulmonary respiratory syncytial virus (RSV) infection decreased Smyd3 expression and Foxp3 expression in Treg leading to increased Il17a. On the other hand, DLL4 supported Il10 expression in vitro and in vivo, which was also partially dependent upon SMYD3. Using genome-wide unbiased mRNA sequencing, novel sets of DLL4- and Smyd3-dependent differentially expressed genes were discovered, including lymphocyte-activation gene 3 (Lag3), a checkpoint inhibitor that has been identified for modulating Th cell activation. Together, our data demonstrate a novel mechanism of DLL4/Notch-induced Smyd3 epigenetic pathways that maintain regulatory CD4 T cells in viral infections.

PMID:
30038214
PMCID:
PMC6160345
DOI:
10.1038/s41385-018-0052-1
[Indexed for MEDLINE]
Free PMC Article

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