Active Demethylation of the <i>Foxp3</i> Locus Leads to the Generation of Stable Regulatory T Cells within the Thymus

DOI PDF 19 Citations 53 References
  • Aras Toker
    Experimental Immunology, Helmholtz Centre for Infection Research , Braunschweig 38124,
  • Dirk Engelbert
    Experimental Rheumatology, Medical Clinic–Rheumatology and Clinical Immunology, Charité University Medicine , Berlin 10117,
  • Garima Garg
    Experimental Immunology, Helmholtz Centre for Infection Research , Braunschweig 38124,
  • Julia K Polansky
    Experimental Immunology, Helmholtz Centre for Infection Research , Braunschweig 38124,
  • Takahisa Miyao
    Research Unit for Immune Homeostasis, RIKEN Research Centre for Allergy and Immunology , Yokohama 230-0045,
  • Stefan Floess
    Experimental Immunology, Helmholtz Centre for Infection Research , Braunschweig 38124,
  • Udo Baron
    Epiontis GmbH , Berlin 12489,
  • Sandra Düber
    Molecular Immunology, Helmholtz Centre for Infection Research , Braunschweig 38124,
  • Robert Geffers
    Genome Analytics, Helmholtz Centre for Infection Research , Braunschweig 38124,
  • Pascal Giehr
    Department of Genetics/Epigenetics, Saarland University , Saarbrücken 66123,
  • Sonja Schallenberg
    Deutsche Forschungsgemeinschaft–Center for Regenerative Therapies Dresden 01307, Dresden,
  • Sven Olek
    Epiontis GmbH , Berlin 12489,
  • Karsten Kretschmer
    Deutsche Forschungsgemeinschaft–Center for Regenerative Therapies Dresden 01307, Dresden,
  • Jörn Walter
    Department of Genetics/Epigenetics, Saarland University , Saarbrücken 66123,
  • Siegfried Weiss
    Molecular Immunology, Helmholtz Centre for Infection Research , Braunschweig 38124,
  • Alf Hamann
    Experimental Rheumatology, Medical Clinic–Rheumatology and Clinical Immunology, Charité University Medicine , Berlin 10117,
  • Shohei Hori
    Research Unit for Immune Homeostasis, RIKEN Research Centre for Allergy and Immunology , Yokohama 230-0045,
  • Jochen Huehn
    Experimental Immunology, Helmholtz Centre for Infection Research , Braunschweig 38124,

Bibliographic Information

Published
2013-04-01
Resource Type
journal article
Rights Information
  • https://academic.oup.com/pages/standard-publication-reuse-rights
DOI
  • 10.4049/jimmunol.1203473
Publisher
Oxford University Press (OUP)

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<jats:title>Abstract</jats:title> <jats:p>Stable expression of Foxp3 in regulatory T cells (Tregs) depends on DNA demethylation at the Treg-specific demethylated region (TSDR), a conserved, CpG-rich region within the Foxp3 locus. The TSDR is selectively demethylated in ex vivo Tregs purified from secondary lymphoid organs, but it is unclear at which stage of Treg development demethylation takes place. In this study, we show that commitment to a stable lineage occurred during early stages of murine thymic Treg development by engraving of lineage-specific epigenetic marks in parallel with establishment of a Treg-specific gene expression profile. TSDR demethylation was achieved through an active mechanism and involved enzymes of the ten-eleven-translocation family and hydroxylation of methylated cytosines, a modification that is implicated as an initiating step of mitosis-independent DNA demethylation pathways and has not yet been observed at specific loci during immune cell differentiation. Together, our results demonstrate that initiating TSDR demethylation during early stages of thymic Treg development commences stabilization of Foxp3 expression and guarantees full functionality and long-term lineage stability of Tregs.</jats:p>

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