Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4(+) T cells tolerized by peptide immunotherapy.
Elife
; 32014 Dec 29.
Article
en En
| MEDLINE
| ID: mdl-25546306
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Péptidos
/
Linfocitos T CD4-Positivos
/
Regiones Promotoras Genéticas
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Epigénesis Genética
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Receptor de Muerte Celular Programada 1
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Inmunoterapia
Límite:
Animals
Idioma:
En
Revista:
Elife
Año:
2014
Tipo del documento:
Article
País de afiliación:
Reino Unido