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Interleukin-10 determines viral clearance or persistence in vivo

Nature Medicine volume 12, pages 1301–1309 (2006)Cite this article

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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Figure 1: Increased IL-10 production during persistent viral infection.
Figure 2: Increased levels of virus-specific T cells after Cl 13 infection of IL-10–deficient mice.
Figure 3: Sustained effector T cell responses in the absence of IL-10.
Figure 4: Increased IL-10 potentiates viral persistence.
Figure 5: Rapid clearance of persistent viral infection facilitates memory T-cell development.
Figure 6: Treatment with antibody to IL-10R to prevent or treat persistent viral infection.

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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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Authors and Affiliations

  1. Molecular and Integrative Neuroscience Department, Viral Immunobiology Laboratory, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    David G Brooks, Matthew J Trifilo, Kurt H Edelmann, Dorian B McGavern & Michael B A Oldstone

  2. Department of Immunology, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Luc Teyton

  3. The Harold L. Dorris Neurological Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Dorian B McGavern

  4. Department of Infectology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Michael B A Oldstone

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Correspondence to David G Brooks.

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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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