Antigen amount dictates CD8+ T-cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell.
Chronic viral infections lead to CD8(+)  T-cell exhaustion, characterized by impaired cytokine secretion and loss of proliferative capacity. While viral load and T-cell dysfunction correlate, it is currently unclear whether the quality of a cell type presenting antigen determines the degree of T-cell exhaustion or if the overall amount of antigen recognized by T cells promotes exhaustion. We found that chronic lymphocytic chorio-meningitis virus infection led to decreased CD8(+)  T-cell exhaustion in DC-MHC class I (MHCI) mice, in which CD8(+)  T cells can only recognize antigen on DCs. However, this increase in CD8(+)  T-cell function came at the expense of fatal immunopathology. Additional antigen recognition on nonhematopoietic cells in DC-MHCI mice promoted T-cell exhaustion and avoidance of immunopathology. Likewise, increased numbers of antigen-expressing hematopoietic cells, as well as a selective elevation of the number of DCs as the only cell type presenting antigen in DC-MHCI mice, resulted in compromised T-cell function. These results favor a scenario in which the overall amount of antigen exposure, rather than the type of cell engaging with virus-specific CD8(+)  T cells, is responsible for their functional exhaustion. Furthermore, exhaustion of virus-specific CD8(+)  T cells leads to avoidance of life-threatening immunopathology.
Institute of Microbiology, ETH Zurich, Zurich, Switzerland.
Kirsten
K
Richter
Thomas
T
Brocker
Annette
A
Oxenius
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002908:Chronic Disease; D003713:Dendritic Cells / Q000276:immunology; D005805:Genes, MHC Class I; D007167:Immunotherapy / Q000379:methods; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019562:Viral Load / Q000276:immunology
D000956:Antigens, Viral