{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T02:13:59Z","timestamp":1792721639643,"version":"4.5.0"},"reference-count":27,"publisher":"National Academy of Sciences","issue":"33","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,8,17]]},"abstract":"<jats:p>Inhibitory receptors play a crucial role in regulating CD8 T-cell function during chronic viral infection. T-cell Ig- and mucin-domain\u2013containing molecule\u20133 (Tim-3) is well known to negatively regulate T-cell responses, but its role in CD8 T-cell exhaustion during chronic infection in vivo remains unclear. In this study, we document coregulation of CD8 T cell exhaustion by Tim-3 and PD-1 during chronic lymphocytic choriomeningitis virus infection. Whereas Tim-3 was only transiently expressed by CD8 T cells after acute infection, virus-specific CD8 T cells retained high Tim-3 expression throughout chronic infection. The majority (approximately 65% to 80%) of lymphocytic choriomeningitis virus\u2013specific CD8 T cells in lymphoid and nonlymphoid organs coexpressed Tim-3 and PD-1. This coexpression of Tim-3 and PD-1 was associated with more severe CD8 T-cell exhaustion in terms of proliferation and secretion of effector cytokines such as IFN-\u03b3, TNF-\u03b1, and IL-2. Interestingly, CD8 T cells expressing both inhibitory receptors also produced the suppressive cytokine IL-10. Most importantly, combined blockade of Tim-3 and PD-1 pathways in vivo synergistically improved CD8 T cell responses and viral control in chronically infected mice. Taken together, our study defines a parameter for determining the severity of CD8 T cell dysfunction and for identifying virus-specific CD8 T cells that produce IL-10, and shows that targeting both PD-1 and Tim-3 is an effective immune strategy for treating chronic viral infections.<\/jats:p>","DOI":"10.1073\/pnas.1009731107","type":"journal-article","created":{"date-parts":[[2010,8,2]],"date-time":"2010-08-02T23:35:49Z","timestamp":1280792149000},"page":"14733-14738","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":799,"title":["Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection"],"prefix":"10.1073","volume":"107","author":[{"given":"Hyun-Tak","family":"Jin","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":"Ana C.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy G.","family":"Tan","sequence":"additional","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":"Erin E.","family":"West","sequence":"additional","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":"Sang-Jun","family":"Ha","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, College of Life Science and Engineering, Yonsei University, Seoul 120-749, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Araki","sequence":"additional","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":"Gordon J.","family":"Freeman","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay K.","family":"Kuchroo","sequence":"additional","affiliation":[{"name":"Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;"}],"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 30322;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2010,8,2]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.11.5535-5545.2004"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2007.06.004"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04444"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.26.021607.090331"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1443"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07662"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2009.01.010"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.09.006"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1679"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/415536a"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2009.00772.x"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20081398"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00639-09"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.8.4911-4927.2003"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.2.1274"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.5.3265"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.9.5450"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.2.688"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0050100"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.14.8960-8968.2005"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01579-09"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2106"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1271"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0803673"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20061792"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni988"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.160.2.521"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1009731107","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T19:26:09Z","timestamp":1649791569000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1009731107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,8,2]]},"references-count":27,"journal-issue":{"issue":"33","published-print":{"date-parts":[[2010,8,17]]}},"alternative-id":["10.1073\/pnas.1009731107"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1009731107","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,8,2]]},"assertion":[{"value":"2010-08-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}