Type I IFN Modulates Innate and Specific Antiviral Immunity

• Published in: The Journal of immunology (1950) 2000-04, Vol.164 (8), p.4220-4228
• Main Authors: Durbin, Joan E, Fernandez-Sesma, Ana, Lee, Chien-Kuo, Rao, T. Dharma, Frey, Alan B, Moran, Thomas M, Vukmanovic, Stanislav, Garcia-Sastre, Adolfo, Levy, David E
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - physiology; Animals; Antibodies, Viral - biosynthesis; Bone Marrow Cells - immunology; Bone Marrow Cells - metabolism; Cells, Cultured; Cytokines - biosynthesis; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; g-Interferon; Immunity, Innate - genetics; Immunity, Innate - immunology; Influenza A virus - immunology; Interferon Type I - physiology; Lung - immunology; Lung - metabolism; Lung - virology; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Orthomyxoviridae Infections - genetics; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - pathology; Orthomyxoviridae Infections - virology; Signal Transduction - genetics; Signal Transduction - immunology; STAT1 Transcription Factor; Trans-Activators - deficiency; Trans-Activators - genetics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.164.8.4220

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.