title: Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8(+) T cells.
abstract: Functionally exhausted T cells have high expression of the PD-1 inhibitory receptor, and therapies that block PD-1 signaling show promise for resolving chronic viral infections and cancer. By using human and murine systems of acute and chronic viral infections, we analyzed epigenetic regulation of PD-1 expression during CD8(+) T cell differentiation. During acute infection, naive to effector CD8(+) T cell differentiation was accompanied by a transient loss of DNA methylation of the Pdcd1 locus that was directly coupled to the duration and strength of T cell receptor signaling. Further differentiation into functional memory cells coincided with Pdcd1 remethylation, providing an adapted program for regulation of PD-1 expression. In contrast, the Pdcd1 regulatory region was completely demethylated in exhausted CD8(+) T cells and remained unmethylated even when virus titers decreased. This lack of DNA remethylation leaves the Pdcd1 locus poised for rapid expression, potentially providing a signal for premature termination of antiviral functions.
authors.affiliation: Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Youngblood
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Oestreich
authors.forename: Sang-Jun
authors.initials: SJ
authors.lastname: Ha
authors.forename: Jaikumar
authors.initials: J
authors.lastname: Duraiswamy
authors.forename: Rama S
authors.initials: RS
authors.lastname: Akondy
authors.forename: Erin E
authors.initials: EE
authors.lastname: West
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Wei
authors.forename: Peiyuan
authors.initials: P
authors.lastname: Lu
authors.forename: James W
authors.initials: JW
authors.lastname: Austin
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Boss
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D002908:Chronic Disease; D019175:DNA Methylation; D057890:Epigenomics; D006801:Humans; D007156:Immunologic Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014777:Virus Diseases / Q000473:pathology*
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; C105992:PDCD1 protein, human; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor