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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;
§
Childrens 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-
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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