Abstract
Persistent viral infections are a major health concern. One obstacle inhibiting the clearance of persistent infections is functional inactivation of antiviral T cells. Although such immunosuppression occurs rapidly after infection, the mechanisms that induce the loss of T-cell activity and promote viral persistence are unknown. Herein we document that persistent viral infection in mice results in a significant upregulation of interleukin (IL)-10 by antigen-presenting cells, leading to impaired T-cell responses. Genetic removal of Il10 resulted in the maintenance of robust effector T-cell responses, the rapid elimination of virus and the development of antiviral memory T-cell responses. Therapeutic administration of an antibody that blocks the IL-10 receptor restored T-cell function and eliminated viral infection. Thus, we identify a single molecule that directly induces immunosuppression leading to viral persistence and demonstrate that a therapy to neutralize IL-10 results in T-cell recovery and the prevention of viral persistence.
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Acknowledgements
We thank H. Lewicki, D. Young and J. Wheatley for technical assistance and F. Chisari for analysis of sALT levels. Independent findings of IL-10R blockade controlling persistent infection were also found by Ejrneas et al. (JEM, in press). Our work was supported by NIH training grant AI07244-22 (D.G.B.), NIH grants AI09484, AI45927 (M.B.A.O.), AI062718-01 (D.B.M.), NS048866-01 (D.B.M.) and a Dana Foundation grant (D.B.M.). This is publication number 18209-MIND from the Viral Immunobiology Laboratory, Department of Molecular and Integrative Neuroscience.
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Supplementary information
Supplementary Fig. 1
Increased IL-10 production by CD4 T cells early during Cl 13 infection. (PDF 275 kb)
Supplementary Fig. 2
Expression of IL-10 receptor during LCMV infection. (PDF 307 kb)
Supplementary Fig. 3
PD-1 and Foxp3 expression by T cells during LCMV infection. (PDF 465 kb)
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Brooks, D., Trifilo, M., Edelmann, K. et al. Interleukin-10 determines viral clearance or persistence in vivo. Nat Med 12, 1301–1309 (2006). https://doi.org/10.1038/nm1492
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DOI: https://doi.org/10.1038/nm1492
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