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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 PD1. Epigenetic changes at the Pdcd1 locus therefore determine the tolerizing potential of TCR-ligation.

Original languageEnglish
Number of pages37
JournaleLIFE
Volume3
Early online date29 Dec 2014
DOIs
Publication statusPublished - 29 Dec 2014

Keywords

  • EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS
  • CHRONIC VIRAL-INFECTION
  • DENDRITIC CELLS
  • IN-VIVO
  • PROGRAMMED DEATH-1
  • CLONAL EXPANSION
  • PHOSPHATASE SHP2
  • SELECTIN LIGAND
  • DNA METHYLATION
  • TOLERANCE

Fingerprint

Dive into the research topics of 'Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4(+) T cells tolerized by peptide immunotherapy'. Together they form a unique fingerprint.

Cite this