{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T07:48:46Z","timestamp":1790322526112,"version":"4.1.0"},"reference-count":37,"publisher":"American Society for Microbiology","issue":"19","license":[{"start":{"date-parts":[[2016,10,1]],"date-time":"2016-10-01T00:00:00Z","timestamp":1475280000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["E00024"],"award-info":[{"award-number":["E00024"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NHS | National Institutes of Health","award":["RO1 AI30048"],"award-info":[{"award-number":["RO1 AI30048"]}]},{"name":"NHS | National Institutes of Health","award":["PO1 AI056299"],"award-info":[{"award-number":["PO1 AI056299"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2016,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>PD-1 is an inhibitory receptor that has a major role in T cell dysfunction during chronic infections and cancer. While demethylation of the PD-1 promoter DNA is observed in exhausted T cells isolated from chronically infected individuals, little is known about when this stable demethylation of PD-1 promoter DNA is programmed during the course of a chronic infection. To assess if PD-1 promoter DNA demethylation is impacted by prolonged stimulation during effector phase of chronic infection, we adoptively transferred virus-specific day 8 effector CD8 T cells from mice infected with lymphocytic choriomeningitis virus (LCMV) clone 13 into recipient mice that had cleared an acute infection. We observed that LCMV-specific CD8 T cells from chronically infected mice maintained their surface expression of PD-1 even after transfer into acute immune mice until day 45 posttransfer. Interestingly, the PD-1 transcriptional regulatory region continued to remain unmethylated in these donor CD8 T cells generated from a chronic infection. The observed maintenance of PD-1 surface expression and the demethylated PD-1 promoter were not a result of residual antigen in the recipient mice, because similar results were seen when chronic infection-induced effector cells were transferred into mice infected with a variant strain of LCMV (LCMV V35A) bearing a mutation in the cognate major histocompatibility complex class I (MHC-I) epitope that is recognized by the donor CD8 T cells. Importantly, the maintenance of PD-1 promoter demethylation in memory CD8 T cells was coupled with impaired clonal expansion and higher PD-1 re-expression upon secondary challenge. These data show that the imprinting of the epigenetic program of the inhibitory receptor PD-1 occurs during the effector phase of chronic viral infection.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    Since PD-1 is a major inhibitory receptor regulating T cell dysfunction during chronic viral infection and cancers, a better understanding of the mechanisms that regulate PD-1 expression is important. In this work, we demonstrate that the PD-1 epigenetic program in antigen-specific CD8 T cells is fixed during the priming phase of chronic infection.\n                  <\/jats:p>","DOI":"10.1128\/jvi.00798-16","type":"journal-article","created":{"date-parts":[[2016,7,27]],"date-time":"2016-07-27T22:58:24Z","timestamp":1469660304000},"page":"8934-8946","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":90,"title":["Demethylation of the PD-1 Promoter Is Imprinted during the Effector Phase of CD8 T Cell Exhaustion"],"prefix":"10.1128","volume":"90","author":[{"given":"Eunseon","family":"Ahn","sequence":"first","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA"},{"name":"Departments of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Youngblood","sequence":"additional","affiliation":[{"name":"Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junghwa","family":"Lee","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA"},{"name":"Departments of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judong","family":"Lee","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA"},{"name":"Departments of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surojit","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics and Pathology, University of Washington School of Medicine, Seattle, Washington, USA"},{"name":"Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafi","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA"},{"name":"Departments of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, 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