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The Journal of Immunology, 2000, 164: 4220-4228.
Copyright © 2000 by The American Association of Immunologists

Type I IFN Modulates Innate and Specific Antiviral Immunity1

Joan E. Durbin*, Ana Fernandez-Sesma, Chien-Kuo Lee*, T. Dharma Rao{dagger}, Alan B. Frey{dagger}, Thomas M. Moran, Stanislav Vukmanovic{ddagger}, Adolfo García-Sastre and David E. Levy2,*

Departments of * Pathology and Kaplan Comprehensive Cancer Center, {dagger} Cell Biology, and {ddagger} Pathology and Heidelberger Division of Immunology, New York University School of Medicine, New York, NY 10016; § Children’s Hospital Research Foundation and Ohio State University Comprehensive Cancer Center, Columbus, OH 43205; and Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029

IFNs protect from virus infection by inducing an antiviral state and by modulating the immune response. Using mice deficient in multiple aspects of IFN signaling, we found that type I and type II IFN play distinct although complementing roles in the resolution of influenza viral disease. Both types of IFN influenced the profile of cytokines produced by T lymphocytes, with a significant bias toward Th2 differentiation occurring in the absence of responsiveness to either IFN. However, although a Th1 bias produced through inhibition of Th2 differentiation by IFN-{gamma} was not required to resolve infection, loss of type I IFN responsiveness led to exacerbated disease pathology characterized by granulocytic pulmonary inflammatory infiltrates. Responsiveness to type I IFN did not influence the generation of virus-specific cytotoxic lymphocytes or the rate of viral clearance, but induction of IL-10 and IL-15 in infected lungs through a type I IFN-dependent pathway correlated with a protective response to virus. Combined loss of both IFN pathways led to a severely polarized proinflammatory immune response and exacerbated disease. These results reveal an unexpected role for type I IFN in coordinating the host response to viral infection and controlling inflammation in the absence of a direct effect on virus replication.




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