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In this study, dynamic changes in histone H3K4 modifications at the Pdcd1 locus during ex vivo and in vivo activation of CD8 T cells suggested a potential role for the histone H3 lysine 4 demethylase LSD1 in regulating PD-1 expression. CD8 T cells lacking LSD1 expressed higher levels of Pdcd1 mRNA following ex vivo stimulation as well as increased surface levels of PD-1 during acute, but not chronic, infection with lymphocytic choriomeningitis virus (LCMV). Blimp-1, a known repressor of PD-1, recruited LSD1 to the Pdcd1 gene during acute, but not chronic, LCMV infection. Loss of DNA methylation at Pdcd1\u2019s promoter-proximal regulatory regions is highly correlated with its expression. However, following acute LCMV infection, in which PD-1 expression levels return to near baseline, LSD1-deficient CD8 T cells failed to remethylate the Pdcd1 locus to the levels of wild-type cells. Finally, in a murine melanoma model, the frequency of PD-1\u2013expressing tumor-infiltrating LSD1-deficient CD8 T cells was greater than in wild type. Thus, LSD1 is recruited to the Pdcd1 locus by Blimp-1, downregulates PD-1 expression by facilitating the removal of activating histone marks, and is important for remethylation of the locus. Together, these data provide insight into the complex regulatory mechanisms governing T cell immunity and regulation of a critical T cell checkpoint gene.<\/jats:p>","DOI":"10.4049\/jimmunol.1900601","type":"journal-article","created":{"date-parts":[[2019,12,6]],"date-time":"2019-12-06T16:55:16Z","timestamp":1575651316000},"page":"449-458","source":"Crossref","is-referenced-by-count":34,"title":["PD-1 Expression during Acute Infection Is Repressed through an LSD1\u2013Blimp-1 Axis"],"prefix":"10.1093","volume":"204","author":[{"given":"Alexander P R","family":"Bally","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; and Emory Vaccine Center, Emory University School of Medicine , Atlanta, GA 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis K","family":"Neeld","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; and Emory Vaccine Center, Emory University School of Medicine , Atlanta, GA 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyuan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; and Emory Vaccine Center, Emory University School of Medicine , Atlanta, GA 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parimal","family":"Majumder","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; and Emory Vaccine Center, Emory University School of Medicine , Atlanta, GA 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9114-6536","authenticated-orcid":false,"given":"Yan","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; and Emory Vaccine Center, Emory University School of Medicine , Atlanta, GA 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9810-3566","authenticated-orcid":false,"given":"Benjamin G","family":"Barwick","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; and Emory Vaccine Center, Emory University School of Medicine , Atlanta, GA 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; and Emory Vaccine Center, Emory University School of Medicine , Atlanta, GA 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2432-1840","authenticated-orcid":false,"given":"Jeremy M","family":"Boss","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; and Emory Vaccine Center, Emory University School of Medicine , Atlanta, GA 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,1,15]]},"reference":[{"key":"2025030417510437500_r1","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nature04444","article-title":"Restoring function in exhausted CD8 T cells during chronic viral infection","volume":"439","author":"Barber","year":"2006","journal-title":"Nature"},{"key":"2025030417510437500_r2","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.immuni.2011.06.015","article-title":"Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8(+) T cells","volume":"35","author":"Youngblood","year":"2011","journal-title":"Immunity"},{"key":"2025030417510437500_r3","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1038\/nature05115","article-title":"PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression","volume":"443","author":"Day","year":"2006","journal-title":"Nature"},{"key":"2025030417510437500_r4","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1038\/nm1482","article-title":"Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. 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