Control of virus-specific CD8+ T-cell exhaustion and immune-mediated pathology by E3 ubiquitin ligase Cbl-b during chronic viral infection.
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.
Ou
Rong
R
Center for Molecular Chaperones/Radiobiology and Cancer Virology, Medical College of Georgia, 1410 Laney Walker Blvd., Augusta, GA 30912, USA.
Zhang
Menghua
M
Huang
Lei
L
Moskophidis
Demetrius
D
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000276:immunology*; D019264:Adoptive Transfer; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology* / Q000473:pathology*; D001219:Aspartate Aminotransferases / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D008099:Liver / Q000473:pathology; D008212:Lymphocyte Depletion; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency / Q000276:immunology*; D016019:Survival Analysis
D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; D050721:Proto-Oncogene Proteins c-cbl; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase