title: Type I IFN modulates innate and specific antiviral immunity.
abstract: 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.
authors.affiliation: Departments of Pathology and Kaplan Comprehensive Cancer Center, Cell Biology, and Pathology and Heidelberger Division of Immunology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Durbin
authors.forename: A
authors.initials: A
authors.lastname: Fernandez-Sesma
authors.forename: C K
authors.initials: CK
authors.lastname: Lee
authors.forename: T D
authors.initials: TD
authors.lastname: Rao
authors.forename: A B
authors.initials: AB
authors.lastname: Frey
authors.forename: T M
authors.initials: TM
authors.lastname: Moran
authors.forename: S
authors.initials: S
authors.lastname: Vukmanovic
authors.forename: A
authors.initials: A
authors.lastname: García-Sastre
authors.forename: D E
authors.initials: DE
authors.lastname: Levy
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology*; D007370:Interferon Type I / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D016207:Cytokines; D004268:DNA-Binding Proteins; D007370:Interferon Type I; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators