I12 Interferons: Overlooked regulators of innate and adaptive immune responses

Abstract

Type I IFNs, that include the IFN- α s and IFN-s, are critical effectors of the host antiviral immune response. Much attention has focused on their direct antiviral effects against viruses in infected tissues, examining specific signaling cascades and effector molecules induced by these IFNs that mediate virus inhibition and protection from infection. To date, their activities as modulators of innate and adaptive immune responses have been largely overlooked, perhaps contributing to their limited clinical application as therapeutics for acute viral infections. Our early studies using IFN-s -/- mice revealed diverse consequences of IFN-s for both the innate and adaptive arms of immunity: altered splenic architecture in IFN-s -/- mice and a reduction in resident macrophages; a defect in B cell maturation; circulating IgM-, Mac-1-, and Gr-1-positive cells are also substantially decreased in IFN-s -/- mice. The decrease in the numbers of circulating macrophages and granulocytes likely reflects defective maturation of primitive BM hematopoiesis in mice, shown by a reduction in CFU-GM. Viewed together, these data indicate that IFN-s is required during different stages of maturation in the development of the immune system. Constant immunosurveillance in the host requires that lymphocytes traffic through lymph nodes (LNs) to sample antigen. pDCs and lymphocytes use similar mechanisms for retention within LNs and we provided evidence that these processes are influenced by IFN-s, even in the absence of viral infection, implicating IFN-s in affecting critical APC-T cell interactions that determine a robust immune response to pathogen infection. Most recently, we have conducted studies in mice infected intranasally with different strains of influenza A virus and show that clearance of virus mediated by IFN-s is associated with polarization of CD4 and CD8 T cells to a Th1 phenotype, increased DC infiltrates into the lungs and dLNs of infected mice, reduced eosinophilia, and a reduction in a novel antigen presenting cell population associated with type 2 immunity and lung immunopathology. Viewed in conjunction with data that suggest an adjuvant role for IFNs in vaccination, accumulating evidence suggests that the immunomodulatory activities of type I IFNs contribute significantly to their antiviral effectiveness.