A Dominant Role for the Methyl-CpG-binding Protein Mbd2 in Controlling Th2 Induction by Dendritic Cells

Overview

Journal Nat Commun

Specialty Biology

Date 2015 Apr 25

PMID 25908537

Citations 43

Authors

Peter C Cook

Heather Owen

Aimee M Deaton

Jessica G Borger

Sheila L Brown

Thomas Clouaire

Gareth-Rhys Jones

Lucy H Jones

Rachel J Lundie

Angela K Marley

Vicky L Morrison

Alexander T Phythian-Adams

Elisabeth Wachter

Lauren M Webb

Tara E Sutherland

Graham D Thomas

John R Grainger

Jim Selfridge

Andrew N J McKenzie

Judith E Allen

Susanna C Fagerholm

Rick M Maizels

Alasdair C Ivens

Adrian Bird

Andrew S MacDonald

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Jenkins S, Perona-Wright G, Worsley A, Ishii N, MacDonald A . Dendritic cell expression of OX40 ligand acts as a costimulatory, not polarizing, signal for optimal Th2 priming and memory induction in vivo. J Immunol. 2007; 179(6):3515-23. DOI: 10.4049/jimmunol.179.6.3515. View

Hendrich B, Guy J, Ramsahoye B, WILSON V, Bird A . Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev. 2001; 15(6):710-23. PMC: 312657. DOI: 10.1101/gad.194101. View

Alvarez-Errico D, Vento-Tormo R, Sieweke M, Ballestar E . Epigenetic control of myeloid cell differentiation, identity and function. Nat Rev Immunol. 2014; 15(1):7-17. DOI: 10.1038/nri3777. View

Stober C, Brode S, White J, Popoff J, Blackwell J . Slc11a1, formerly Nramp1, is expressed in dendritic cells and influences major histocompatibility complex class II expression and antigen-presenting cell function. Infect Immun. 2007; 75(10):5059-67. PMC: 2044529. DOI: 10.1128/IAI.00153-07. View

Artis D, Kane C, Fiore J, Zaph C, Shapira S, Joyce K . Dendritic cell-intrinsic expression of NF-kappa B1 is required to promote optimal Th2 cell differentiation. J Immunol. 2005; 174(11):7154-9. DOI: 10.4049/jimmunol.174.11.7154. View

Song L, Lee C, Schindler C . Deletion of the murine scavenger receptor CD68. J Lipid Res. 2011; 52(8):1542-50. PMC: 3137020. DOI: 10.1194/jlr.M015412. View

Guy J, Hendrich B, Holmes M, Martin J, Bird A . A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet. 2001; 27(3):322-6. DOI: 10.1038/85899. View

Perona-Wright G, Jenkins S, OConnor R, Zienkiewicz D, McSorley H, Maizels R . A pivotal role for CD40-mediated IL-6 production by dendritic cells during IL-17 induction in vivo. J Immunol. 2009; 182(5):2808-15. DOI: 10.4049/jimmunol.0803553. View

Merad M, Sathe P, Helft J, Miller J, Mortha A . The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol. 2013; 31:563-604. PMC: 3853342. DOI: 10.1146/annurev-immunol-020711-074950. View

10.

MacDonald A, Straw A, Bauman B, Pearce E . CD8- dendritic cell activation status plays an integral role in influencing Th2 response development. J Immunol. 2001; 167(4):1982-8. DOI: 10.4049/jimmunol.167.4.1982. View

11.

Williams J, Tjota M, Clay B, Vander Lugt B, Bandukwala H, Hrusch C . Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation. Nat Commun. 2013; 4:2990. PMC: 4003872. DOI: 10.1038/ncomms3990. View

12.

MacDonald A, Maizels R . Alarming dendritic cells for Th2 induction. J Exp Med. 2008; 205(1):13-7. PMC: 2234366. DOI: 10.1084/jem.20072665. View

13.

Hutchins A, Mullen A, Lee H, Sykes K, High F, Hendrich B . Gene silencing quantitatively controls the function of a developmental trans-activator. Mol Cell. 2002; 10(1):81-91. DOI: 10.1016/s1097-2765(02)00564-6. View

14.

Larkin B, Smith P, Ponichtera H, Shainheit M, Rutitzky L, Stadecker M . Induction and regulation of pathogenic Th17 cell responses in schistosomiasis. Semin Immunopathol. 2012; 34(6):873-88. PMC: 3690599. DOI: 10.1007/s00281-012-0341-9. View

15.

Martinez-Pomares L . The mannose receptor. J Leukoc Biol. 2012; 92(6):1177-86. DOI: 10.1189/jlb.0512231. View

16.

Hutchins A, Artis D, Hendrich B, Bird A, Scott P, Reiner S . Cutting edge: a critical role for gene silencing in preventing excessive type 1 immunity. J Immunol. 2005; 175(9):5606-10. DOI: 10.4049/jimmunol.175.9.5606. View

17.

Kool M, Hammad H, Lambrecht B . Cellular networks controlling Th2 polarization in allergy and immunity. F1000 Biol Rep. 2012; 4:6. PMC: 3292286. DOI: 10.3410/B4-6. View

18.

Maric M, Arunachalam B, Phan U, Dong C, GARRETT W, Cannon K . Defective antigen processing in GILT-free mice. Science. 2001; 294(5545):1361-5. DOI: 10.1126/science.1065500. View

19.

Bell B, Kitajima M, Larson R, Stoklasek T, Dang K, Sakamoto K . The transcription factor STAT5 is critical in dendritic cells for the development of TH2 but not TH1 responses. Nat Immunol. 2013; 14(4):364-71. PMC: 4161284. DOI: 10.1038/ni.2541. View

20.

Gunther K, Rust M, Leers J, Boettger T, Scharfe M, Jarek M . Differential roles for MBD2 and MBD3 at methylated CpG islands, active promoters and binding to exon sequences. Nucleic Acids Res. 2013; 41(5):3010-21. PMC: 3597697. DOI: 10.1093/nar/gkt035. View