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Journal of Virology, April 2008, p. 3353-3368, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.01350-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Control of Virus-Specific CD8⁺ T-Cell Exhaustion and Immune-Mediated Pathology by E3 Ubiquitin Ligase Cbl-b during Chronic Viral Infection

Center for Molecular Chaperones/Radiobiology and Cancer Virology, Medical College of Georgia, Augusta, Georgia 30912

Received 20 June 2007/ Accepted 2 January 2008

A characteristic feature in the immune response to many persistent viral infections is the dysfunction or deletion of antigen-specific T cells (exhaustion). 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^–/– mice infected with a low dose of LCMV Docile mount a strong CD8⁺ T-cell response that rapidly clears the infection, and the animals remain healthy; in contrast, down-regulation of the epitope-specific CD8⁺ T-cell population in persistently infected Cbl-b^–/– 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^–/– 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.

Published ahead of print on 16 January 2008.