Type IIFN modulates innate and specific antiviral immunity

IFNs protect from virus infection by inducing an antiviral state and by mod ulating the immune response. Using mice deficient in multiple aspects of IF N signaling, we found that type I and type II IFN play distinct although co mplementing 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 r esponsiveness to either HN, However, although a Th1 bias produced through i nhibition of Th2 differentiation by IFN-gamma was not required to resolve i nfection, loss of type I IFN responsiveness led to exacerbated disease path ology characterized by granulocytic pulmonary inflammatory infiltrates. Res ponsiveness to type I IFN did not influence the generation;of virus-specifi c 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 corr elated with a protective response to virus. Combined loss of both IFN pathw ays led to a severely polarized proinflammatory immune response and exacerb ated disease, These results reveal an unexpected role for type I IFN in coo rdinating the host response to viral infection and controlling inflammation in the absence of a direct effect on virus replication. The Journal of Imm unology, 2000, 164: 4220-4228.