title: A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells.
abstract: 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.
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M3 9NT, UK.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Cook
authors.affiliation: Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Owen
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, UK.
authors.forename: Aimée M
authors.initials: AM
authors.lastname: Deaton
authors.affiliation: Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.
authors.forename: Jessica G
authors.initials: JG
authors.lastname: Borger
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M3 9NT, UK.
authors.forename: Sheila L
authors.initials: SL
authors.lastname: Brown
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Clouaire
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M3 9NT, UK.
authors.forename: Gareth-Rhys
authors.initials: GR
authors.lastname: Jones
authors.affiliation: Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.
authors.forename: Lucy H
authors.initials: LH
authors.lastname: Jones
authors.affiliation: Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Lundie
authors.affiliation: Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.
authors.forename: Angela K
authors.initials: AK
authors.lastname: Marley
authors.affiliation: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY UK.
authors.forename: Vicky L
authors.initials: VL
authors.lastname: Morrison
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M3 9NT, UK.
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Phythian-Adams
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, UK.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Wachter
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M3 9NT, UK.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Webb
authors.affiliation: Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.
authors.forename: Tara E
authors.initials: TE
authors.lastname: Sutherland
authors.affiliation: Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.
authors.forename: Graham D
authors.initials: GD
authors.lastname: Thomas
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M3 9NT, UK.
authors.forename: John R
authors.initials: JR
authors.lastname: Grainger
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, UK.
authors.forename: Jim
authors.initials: J
authors.lastname: Selfridge
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge, CB2 0QH UK.
authors.forename: Andrew N J
authors.initials: AN
authors.lastname: McKenzie
authors.affiliation: Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Allen
authors.affiliation: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY UK.
authors.forename: Susanna C
authors.initials: SC
authors.lastname: Fagerholm
authors.affiliation: Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Maizels
authors.affiliation: Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.
authors.forename: Alasdair C
authors.initials: AC
authors.lastname: Ivens
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Bird
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M3 9NT, UK.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: MacDonald
mesh_terms: D000485:Allergens; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016764:Cell Polarity; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics*; D006967:Hypersensitivity / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D039981:Pyroglyphidae / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012550:Schistosoma mansoni / Q000276:immunology; D012555:Schistosomiasis mansoni / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000485:Allergens; D004268:DNA-Binding Proteins; C489326:Mbd2 protein, mouse; D012333:RNA, Messenger