Type I (IFNα and β) and II interferons (IFNγ) play essential roles in promoting innate immunity against a wide variety of pathogens. Although much has been learned in the last 20 years about the molecular and cellular biology of IFN family members and their in vivo activities, we still know very little about the cell-specific actions of the cytokines in vivo, and in particular which cells need to respond to interferons to control infection. The latter issue has been particularly difficult to approach because of the nearly ubiquitous cellular expression of IFNα/β and IFNγ receptors. The overall goal of this project is to generate and characterize genetically homogenous C5BL/6 mice that display tissue specific unresponsiveness to either IFNα/β or IFNγ and to generate and characterize mAb reagents that can distinguish between the forms of Type I IFN, and to use these novel reagents to define in detail how IFNs act in vivo to control infection by a broad range of pathogens.