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

Autor:	McPherson RC; MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom., Konkel JE; MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom., Prendergast CT; MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom., Thomson JP; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Ottaviano R; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Leech MD; MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom., Kay O; MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom., Zandee SE; MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom., Sweenie CH; MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom., Wraith DC; Department of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom., Meehan RR; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Drake AJ; University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom., Anderton SM; MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2014 Dec 29; Vol. 3. Date of Electronic Publication: 2014 Dec 29.
DOI:	10.7554/eLife.03416
Abstrakt:	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.
Databáze:	MEDLINE
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