A NULL MUTATION IN THE GENE ENCODING A TYPE-I INTERFERON RECEPTOR COMPONENT ELIMINATES ANTIPROLIFERATIVE AND ANTIVIRAL RESPONSES TO INTERFERON-ALPHA AND INTERFERON-BETA AND ALTERS MACROPHAGE RESPONSES

To examine the in vivo role(s) of type I interferons (IFNs) and to determine the role of a component of the type I IFN receptor (IFNAR1) in mediating responses to these IFNs, we generated mice with a null mutation (-/-) in the IFNAR1 gene. Despite compelling evidence for modulation of cell proliferation and differentiation by type I IFNs, there were no gross signs of abnormal fetal development or morphological changes in adult IFNAR1 -/- mice. However, abnormalities of hemopoietic cells were detected in IFNAR1 -/- mice, Elevated levels of myeloid lineage cells were detected in peripheral blood and bone marrow by staining with Mac-1 and Gr-1 antibodies, Furthermore, bone marrow macrophages from IFNAR1 -/- mice showed abnormal responses to colony-stimulating factor 1 and lipopolgsaccharide. IFNAR1 -/- mice were highly susceptible to viral infection: viral titers were undetected 24 hr after infection of IFNAR1 +/+ mice but were extremely high in organs of IFNAR1 -/- mice, demonstrating that the type I IFN system is a major acute antiviral defence, In cell lines derived from IFNAR1 -/- mice, there was no signaling in response to IFN-alpha or -beta as measured by induction of 2'-5' oligooadenylate synthetase, antiviral, or antiproliferative responses. Importantly, these studies demonstrate that type I IFNs function in the development and responses of myeloid lineage cells, particularly macrophages, and that the LFNAR1 receptor component is essential for antiproliferative and antiviral responses to IFN-alpha and -beta.