title: Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4(+) T cells tolerized by peptide immunotherapy.
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.
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Rhoanne C
authors.initials: RC
authors.lastname: McPherson
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Konkel
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Catriona T
authors.initials: CT
authors.lastname: Prendergast
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: John P
authors.initials: JP
authors.lastname: Thomson
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ottaviano
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Melanie D
authors.initials: MD
authors.lastname: Leech
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kay
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Stephanie E J
authors.initials: SE
authors.lastname: Zandee
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Claire H
authors.initials: CH
authors.lastname: Sweenie
authors.affiliation: Department of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: David C
authors.initials: DC
authors.lastname: Wraith
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Meehan
authors.affiliation: University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Drake
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Anderton
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D003470:Culture Media; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000008:administration & dosage*; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: D003470:Culture Media; C105992:PDCD1 protein, human; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine
keywords: PD-1; immune tolerance; immunology; mouse; t cells