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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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    Rights statement: © 2014, McPherson et al This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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

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.

    Research areas

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

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