Institute of Microbiology, ETH Zurich, Zurich, Switzerland.
Eur J Immunol. 2012 Sep;42(9):2290-304. doi: 10.1002/eji.201142275. Epub 2012 Aug 6.
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.
慢性病毒感染导致 CD8(+) T 细胞衰竭，其特征是细胞因子分泌受损和增殖能力丧失。虽然病毒载量和 T 细胞功能障碍相关，但目前尚不清楚是呈递抗原的细胞类型的质量决定了 T 细胞衰竭的程度，还是 T 细胞识别的总的抗原量促进了衰竭。我们发现，慢性淋巴细胞性脉络丛脑膜炎病毒感染导致 DC-MHC I (MHCI) 小鼠中 CD8(+) T 细胞衰竭减少，其中 CD8(+) T 细胞只能识别 DC 上的抗原。然而，这种 CD8(+) T 细胞功能的增加是以致命性免疫病理学为代价的。在 DC-MHCI 小鼠的非造血细胞上额外的抗原识别促进了 T 细胞衰竭并避免了免疫病理学。同样，增加表达抗原的造血细胞数量，以及在 DC-MHCI 小鼠中选择性地增加作为唯一呈递抗原的 DC 数量，导致 T 细胞功能受损。这些结果表明，总的抗原暴露量，而不是与病毒特异性 CD8(+) T 细胞相互作用的细胞类型，决定了它们的功能衰竭。此外，病毒特异性 CD8(+) T 细胞的衰竭导致避免危及生命的免疫病理学。
