Interleukin-10 determines viral clearance or persistence in vivo.
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.
Brooks
David G
DG
Viral Immunobiology Laboratory, Molecular and Integrative Neuroscience Department, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. dbrooks@scripps.edu
Trifilo
Matthew J
MJ
Edelmann
Kurt H
KH
Teyton
Luc
L
McGavern
Dorian B
DB
Oldstone
Michael B A
MB
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005434:Flow Cytometry; D006678:HIV / Q000502:physiology*; D016174:Hepacivirus / Q000502:physiology*; D007156:Immunologic Memory; D016753:Interleukin-10 / Q000502:physiology*; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology*; D051379:Mice; D053701:Receptors, Interleukin-10 / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction
D053701:Receptors, Interleukin-10; D016753:Interleukin-10