{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T01:36:02Z","timestamp":1791509762339,"version":"4.3.4"},"reference-count":33,"publisher":"National Academy of Sciences","issue":"21","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,5,26]]},"abstract":"<jats:p>\n                    Many persistent viral infections induce dysfunctional T cell responses. Although a negative correlation exists between viral load and T cell responses during chronic infection, it is not known whether high antigen levels are the cause or just the consequence of T cell exhaustion. Furthermore, it is unclear what role antigen presentation by bone-marrow (BM) derived versus infected parenchymal cells has on T cell exhaustion. To address these issues, we examined the influence of antigen presentation by different cell types on CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell responses during persistent infection of mice with lymphocytic choriomeningitis virus (LCMV) clone 13. We generated BM chimeric mice, in which non-BM derived cells were MHC class I deficient. Virus-specific CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in lymphoid and nonlymphoid tissues were increased in both number and ability to produce cytokines in these mice soon after infection. However, viral clearance from infected MHC I\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    parenchyma was significantly impaired, despite increased populations of cytokine producing CTL. The CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell response was overwhelmed by sustained antigen persistence, becoming increasingly exhausted within 4\u20136 weeks. Thus, we find that (\n                    <jats:italic>i<\/jats:italic>\n                    ) sustained antigen presentation directly drives T cell exhaustion during a chronic viral infection, (\n                    <jats:italic>ii<\/jats:italic>\n                    ) CTL require direct antigen-MHC interactions to clear virus-infected cells, and (\n                    <jats:italic>iii<\/jats:italic>\n                    ) persistent interactions with antigen presented on both hematopoietic and nonhematopoietic cells negatively impacts virus-specific T cell responses during chronic infection.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0809818106","type":"journal-article","created":{"date-parts":[[2009,5,11]],"date-time":"2009-05-11T21:43:15Z","timestamp":1242078195000},"page":"8623-8628","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":366,"title":["High antigen levels are the cause of T cell exhaustion during chronic viral infection"],"prefix":"10.1073","volume":"106","author":[{"given":"Scott N.","family":"Mueller","sequence":"first","affiliation":[{"name":"Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafi","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 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