Cook Peter C, Owen Heather, Deaton Aimée M, Borger Jessica G, Brown Sheila L, Clouaire Thomas, Jones Gareth-Rhys, Jones Lucy H, Lundie Rachel J, Marley Angela K, Morrison Vicky L, Phythian-Adams Alexander T, Wachter Elisabeth, Webb Lauren M, Sutherland Tara E, Thomas Graham D, Grainger John R, Selfridge Jim, McKenzie Andrew N J, Allen Judith E, Fagerholm Susanna C, Maizels Rick M, Ivens Alasdair C, Bird Adrian, MacDonald Andrew S
Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M3 9NT, UK.
Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.
Nat Commun. 2015 Apr 24;6:6920. doi: 10.1038/ncomms7920.
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.
树突状细胞（DCs）指导CD4(+) T细胞分化为不同的辅助性（Th）亚群，这些亚群是抵御各种感染所必需的。然而，DCs促进Th2反应的机制目前尚不清楚，而Th2反应对抵抗蠕虫感染的免疫和过敏性疾病都很重要。我们证明了蛋白质甲基-CpG结合结构域2（Mbd2）在调节一系列与最佳DC激活和功能相关的基因表达中起关键作用，Mbd2将DNA甲基化与抑制性染色质结构联系起来。在缺乏Mbd2的情况下，DCs表现出表型激活降低，启动针对蠕虫或过敏原的Th2免疫的能力明显受损。这些数据确定了一种表观遗传机制，该机制是DCs激活CD4(+) T细胞反应的核心，特别是在Th2环境中，并揭示甲基-CpG结合蛋白及其控制下的基因可能是2型炎症的治疗靶点。
