1. Immunology and Inflammation
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Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4+ T cells tolerized by peptide immunotherapy

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Cite this article as: eLife 2014;3:e03416 doi: 10.7554/eLife.03416

Abstract

Clinically effective antigen-based immunotherapy must silence antigen-experienced effector T cells (Teff) driving ongoing immune pathology. Using CD4+ autoimmune Teff cells, we demonstrate that peptide immunotherapy (PIT) is strictly dependent upon sustained T cell expression of the co-inhibitory molecule PD-1. We found high levels of 5-hydroxymethylcytosine (5hmC) at the PD-1 (Pdcd1) promoter of non-tolerant T cells. 5hmC was lost in response to PIT, with DNA hypomethylation of the promoter. We identified dynamic changes in expression of the genes encoding the Ten-Eleven-Translocation (TET) proteins that are associated with the oxidative conversion 5-methylcytosine and 5hmC, during cytosine demethylation. We describe a model whereby promoter demethylation requires the co-incident expression of permissive histone modifications at the Pdcd1 promoter together with TET availability. This combination was only seen in tolerant Teff cells following PIT, but not in Teff that transiently express PD-1. Epigenetic changes at the Pdcd1 locus therefore determine the tolerizing potential of TCR-ligation.

Article and author information

Author details

  1. Rhoanne C McPherson

    MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Joanne E Konkel

    MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Catriona T Prendergast

    MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. John P Thomson

    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Raffaele Ottaviano

    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Melanie D Leech

    MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Oliver Kay

    MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Stephanie E J Zandee

    MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Claire H Sweenie

    MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. David C Wraith

    Department of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Richard R Meehan

    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Amanda J Drake

    Endocrinology Unit, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Stephen M Anderton

    MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    steve.anderton@ed.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was approved by the University of Edinburgh Ethical Review Panel and was performed in accordance with UK legislation (PPL 60/4116).

Reviewing Editor

  1. Shimon Sakaguchi, Osaka University, Japan

Publication history

  1. Received: May 19, 2014
  2. Accepted: December 24, 2014
  3. Accepted Manuscript published: December 29, 2014 (version 1)
  4. Version of Record published: January 21, 2015 (version 2)

Copyright

© 2014, McPherson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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