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In a murine model of intravenous hepatotropic adenovirus infection, liver-primed antiviral CD8<jats:sup>+<\/jats:sup> T cells fail to produce proinflammatory cytokines and do not display cytolytic activity characteristic of effector CD8<jats:sup>+<\/jats:sup> T cells generated by infection at an extrahepatic, that is, subcutaneous, site. Importantly, liver-generated CD8<jats:sup>+<\/jats:sup> T cells also appear to have a T-regulatory (T<jats:sub>reg<\/jats:sub>) cell function exemplified by their ability to limit proliferation of antigen-specific T-effector (T<jats:sub>eff<\/jats:sub>) cells <jats:italic toggle=\"yes\">in vitro<\/jats:italic> and <jats:italic toggle=\"yes\">in vivo<\/jats:italic> via T-cell immunoglobulin and mucin 3 (Tim-3) expressed by the CD8<jats:sup>+<\/jats:sup> T<jats:sub>reg<\/jats:sub> cells. Regulatory activity did not require recognition of the canonical Tim-3 ligand, galectin-9, but was dependent on CD8<jats:sup>+<\/jats:sup> T<jats:sub>reg<\/jats:sub> cell-surface Tim-3 binding to the alarmin, high-mobility group box 1 (HMGB-1). <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Virus-specific Tim-3<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup> T cells operating through HMGB-1 recognition in the setting of acute and chronic viral infections of the liver may act to dampen hepatic T-cell responses in the liver microenvironment and, as a consequence, limit immune-mediated tissue injury or promote the establishment of persistent infections. (HEPATOLOGY 2014;59:1351-1365)<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.26938","type":"journal-article","created":{"date-parts":[[2013,11,21]],"date-time":"2013-11-21T00:21:20Z","timestamp":1384993280000},"page":"1351-1365","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":49,"title":["Liver-primed CD8+ T cells suppress antiviral adaptive immunity through galectin-9-independent T-Cell immunoglobulin and mucin 3 engagement of high-mobility group box 1 in mice"],"prefix":"10.1097","volume":"59","author":[{"given":"Joseph S.","family":"Dolina","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Braciale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young 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