A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells.

Peter Cook, Heather Owen, Aimée M Deaton, Jessica G Borger, Sheila Brown, Thomas Clouaire, Gareth-Rhys Jones, Lucy H Jones, Rachel J Lundie, Angela K Marley, Vicky L Morrison, Alexander Phythian-Adams, Elisabeth Wachter, Lauren Webb, Tara Sutherland, Graham D Thomas, John R Grainger, Jim Selfridge, Andrew N J McKenzie, Judith AllenSusanna C Fagerholm, Rick M Maizels, Alasdair C Ivens, Adrian Bird, Andrew S MacDonald

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Dendritic cells (DCs) direct CD4(+) T-cell differentiation into diverse helper (Th) subsets that are required for protection against varied infections. However, the mechanisms used by DCs to promote Th2 responses, which are important both for immunity to helminth infection and in allergic disease, are currently poorly understood. We demonstrate a key role for the protein methyl-CpG-binding domain-2 (Mbd2), which links DNA methylation to repressive chromatin structure, in regulating expression of a range of genes that are associated with optimal DC activation and function. In the absence of Mbd2, DCs display reduced phenotypic activation and a markedly impaired capacity to initiate Th2 immunity against helminths or allergens. These data identify an epigenetic mechanism that is central to the activation of CD4(+) T-cell responses by DCs, particularly in Th2 settings, and reveal methyl-CpG-binding proteins and the genes under their control as possible therapeutic targets for type-2 inflammation.
Original languageEnglish
Article number6920
JournalNature Communications
Publication statusPublished - 24 Apr 2015

Bibliographical note

This work was supported by the M.R.C. (G0701437 to A.S.M.) and the Wellcome Trust, Cancer Research United Kingdom and the B.B.S.R.C (A.B., L.H.J., G-R.J., G.D.T., J.R.G., R.M.M., S.C.F. and V.L.M.). DNA sequencing was managed and performed at the Wellcome Trust Sanger Institute. Illumina BeadChip experiments were performed at the Wellcome Trust Clinical Research Facility, Edinburgh, by Louise Evenden and Lee Murphy. We thank Rinku Rajan for technical support; Yoshihide Kanaoka for advice on the HDM protocol; Martin Waterfall for cell sorting and assistance with flow cytometry; Mark Travis and John Worthington for supplying transforming growth factor-β; and David Gray, Caetano Reis e Sousa, Kevin Couper and Markus Mohrs for provision of IL-10eGFP, CD11cCre and KN2 mice. Schistosome life cycle stages used to generate eggs and SEA for this research were supplied by the N.I.A.I.D. Schistosomiasis Resource Center at the Biomedical Research Institute (Rockville, MD, USA) through Contract N01-AI-30026.


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