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This down-regulation of virus-specific T-cell response represents a critical control mechanism that exists within T-cell activation pathways to prevent lethal disease by inappropriate responses against disseminating virus infections. However, the molecular mechanisms by which the immune system determines whether to mount a full response to such infections remain largely unexplored. Here, we have established that in the murine lymphocytic choriomeningitis virus (LCMV) model, induction of the T-cell receptor signaling inhibitor molecule E3 ligase Cbl-b is critically involved in this decision. In particular, our data revealed that Cbl-b controls the program responsible for T-cell tolerance (exhaustion) induction during a chronic viral infection. Thus, Cbl-b<jats:sup>\u2212\/\u2212<\/jats:sup>mice infected with a low dose of LCMV Docile mount a strong CD8<jats:sup>+<\/jats:sup>T-cell response that rapidly clears the infection, and the animals remain healthy; in contrast, down-regulation of the epitope-specific CD8<jats:sup>+<\/jats:sup>T-cell population in persistently infected Cbl-b<jats:sup>\u2212\/\u2212<\/jats:sup>mice, compared to that in chronically infected B6 mice, was significantly delayed, and this was associated with increased morbidity and eventual death in nearly 20% of the animals. Interestingly, infection of Cbl-b<jats:sup>\u2212\/\u2212<\/jats:sup>mice with a moderate virus dose resulted in rapid death with 100% mortality by 7 to 8 days after infection, caused by a dysregulated antiviral T-cell response, whereas the infected B6 mice survived and remained healthy. In conclusion, our results suggest that Cbl-b is critically involved in T-cell exhaustion and prevention of lethal disease.<\/jats:p>","DOI":"10.1128\/jvi.01350-07","type":"journal-article","created":{"date-parts":[[2008,1,17]],"date-time":"2008-01-17T01:33:48Z","timestamp":1200533628000},"page":"3353-3368","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":38,"title":["Control of Virus-Specific CD8<sup>+<\/sup>T-Cell Exhaustion and Immune-Mediated Pathology by E3 Ubiquitin Ligase Cbl-b during Chronic Viral Infection"],"prefix":"10.1128","volume":"82","author":[{"given":"Rong","family":"Ou","sequence":"first","affiliation":[{"name":"Center for Molecular Chaperones\/Radiobiology and Cancer Virology, Medical College of Georgia, Augusta, Georgia 30912"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Menghua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Molecular Chaperones\/Radiobiology and Cancer Virology, Medical College of Georgia, Augusta, Georgia 30912"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Huang","sequence":"additional","affiliation":[{"name":"Center for Molecular Chaperones\/Radiobiology and Cancer Virology, Medical College of Georgia, Augusta, Georgia 30912"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Demetrius","family":"Moskophidis","sequence":"additional","affiliation":[{"name":"Center for Molecular Chaperones\/Radiobiology and Cancer Virology, Medical College of Georgia, Augusta, Georgia 30912"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0610335104"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0966-842X(00)01830-8"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(03)00084-0"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.1.63"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/35003228"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2007.02.006"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04444"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0166-0934(91)90018-U"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.68.7.4700-4704.1994"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.81920-0"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2006.00370.x"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.1998.tb01206.x"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04079"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1492"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1089\/088282403763635401"},{"key":"e_1_3_2_17_2","unstructured":"Semin. 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