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

Research output: Contribution to journalArticle

Authors

  • Rhoanne C McPherson
  • Joanne E Konkel
  • Catriona T Prendergast
  • John P Thomson
  • Raffaele Ottaviano
  • Melanie D Leech
  • Oliver Kay
  • Stephanie E J Zandee
  • Claire H Sweenie
  • David C Wraith
  • Richard R Meehan
  • Amanda J Drake
  • Stephen M Anderton

Colleges, School and Institutes

External organisations

  • Medical Research Council (MRC) Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
  • MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
  • BRISTOL UNIVERSITY
  • University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

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.

Details

Original languageEnglish
JournalElife
Volume3
Publication statusPublished - 29 Dec 2014

Keywords

  • Animals, CD4-Positive T-Lymphocytes, Culture Media, Cytosine, DNA Methylation, Epigenesis, Genetic, Immunotherapy, Mice, Mice, Inbred C57BL, Peptides, Programmed Cell Death 1 Receptor, Promoter Regions, Genetic, Journal Article, Research Support, Non-U.S. Gov't