期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 124, 期 8, 页码 3455-3468出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JC166108
关键词
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资金
- Australian NHMRC Overseas Biomedical Postdoctoral Fellowship
- Yale School of Medicine Brown-Coxe Postdoctoral Fellowship
- Alexander von Humboldt Foundation
- CIHR
- Howard Hughes Medical Institute and NIH [RO1AI074699]
During the course of many chronic viral infections, the antiviral T cell response becomes attenuated through a process that is regulated in part by the host. While elevated expression of the immunosuppressive cytolcine IL-10 is involved in the suppression of viral-specific T cell responses, the relevant cellular sources of IL-10, as well as the pathways responsible for IL-10 induction, remain unclear. In this study, we traced IL-10 production over the course of chronic lymphocytic choriomeningitis virus (LCMV) infection in an IL-10 reporter mouse line. Using this model, we demonstrated that virus-specific T cells with reduced inflammatory function, particularly Th1 cells, display elevated and sustained IL-10 expression during chronic LCMV infection. Furthermore, ablation of IL-10 from the T cell compartment partially restored T cell function and reduced viral loads in LCMV-infected animals. We found that viral persistence is needed for sustained IL-10 production by Th1 cells and that the transcription factor BLIMP-1 is required for IL-10 expression by Th1 cells. Restimulation of Th1 cells from LCMV-infected mice promoted BLIMP-1 and subsequent IL-10 expression, suggesting that constant antigen exposure likely induces the BLIMP-1/IL-10 pathway during chronic viral infection. Together, these data indicate that effector T cells self-limit their responsiveness during persistent viral infection via an IL-10 dependent negative feedback loop.
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