{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T14:01:46Z","timestamp":1793109706048,"version":"4.5.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2008,10,1]],"date-time":"2008-10-01T00:00:00Z","timestamp":1222819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>PD-1 is a transmembrane protein involved in the regulation of immunological tolerance. Multiple studies have reported an association between high levels of PD-1 expressed on T cell surfaces and exhaustion in lymphocyte populations when challenged by chronic viral infections, such as HIV. By using model systems consisting of murine EL4 cells, which constitutively express PD-1, and primary murine CD8 T cells that express PD-1 upon T cell stimulation, we have identified two tissue-specific hypersensitive sites at the 5\u2032 CR of the PD-1 locus. Gene reporter assays in CD8 T cells have shown that one of these sites has robust transcriptional activity in response to cell stimulation. Cell treatment with the calcineurin inhibitor cyclosporine A or a NFAT-specific inhibitor led to a sharp reduction in PD-1 expression in the constitutive and inducible systems. Furthermore, analysis of this region by chromatin immunoprecipitation assay revealed NFATc1 binding associated with gene activation in EL4 and primary CD8 T cells. Mutation of the NFATc1 binding site in PD-1 reporter constructs resulted in a complete loss of promoter activity. Together, these results demonstrate that PD-1 gene regulation occurs in part via the recruitment of NFATc1 to a novel regulatory element at the pdcd1 locus and provides the molecular mechanism responsible for the induction of PD-1 in response to T cell stimulation.<\/jats:p>","DOI":"10.4049\/jimmunol.181.7.4832","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T19:07:10Z","timestamp":1397848030000},"page":"4832-4839","source":"Crossref","is-referenced-by-count":394,"title":["NFATc1 Regulates PD-1 Expression upon T Cell Activation"],"prefix":"10.1093","volume":"181","author":[{"given":"Kenneth J","family":"Oestreich","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyesuk","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafi","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology"},{"name":"Emory Vaccine Center, Emory University School of Medicine , Atlanta, GA 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy M","family":"Boss","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2008,10,1]]},"reference":[{"key":"2026012807114550200_R1","first-page":"765","article-title":"Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes","volume-title":"Int. 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