Gottfried Alber

Mouse Macrophages Carrying Both Subunits of the Human Interferon-γ (IFN-γ) Receptor Respond to Human IFN-γ but Do Not Acquire Full Protection against Viral Cytopathic Effect

Studies of hamster-human and mouse-human somatic fibroblast hybrids and transfected mouse fibroblasts have demonstrated that signaling through the human interferon-γ receptor (hu-IFN-γR) requires the formation of a complex consisting of ligand (IFN-γ), a ligand binding receptor chain (IFN-γR1), and a signal transducing receptor chain (IFN-γR2). To date, the ability of this receptor complex to transduce the full repertoire of biological signals has been difficult to assess due to the limited number of activities that IFN-γ can exert on fibroblasts. The current report assesses the ability of hu-IFN-γR chains to transduce signals in the absence of background human gene products by expressing hu-IFN-γR2 in a transformed macrophage cell line (F10/96) derived from a hu-IFN-γR1 transgenic mouse. Our results indicate that F10/96 clones expressing both human receptor proteins bind hu-IFN-γ with an affinity comparable to that of human cells. Binding of either human or mouse IFN-γ to its respective receptor elicits classic IFN-γ responses such as up-regulation of major histocompatibility complex antigens, enhanced expression of IRF-1, and increased production of NO2− radicals, interleukin-6, tumor necrosis factor-α, and granulocyte macrophage-colony stimulating factor. However, hu-IFN-γ could not fully protect the clones from cytopathic effects of encephalomyocarditis virus and vesicular stomatitis virus while mo-IFN-γ could. These results demonstrate that while co-expression of hu-IFN-γR1 and hu-IFN-γR2 is necessary and sufficient for most IFN-γ-induced responses, it is not sufficient to confer a generalized antiviral state. These findings further suggest that additional species-specific accessory factor(s) are necessary for full signaling potential through the IFN-γ receptor complex. The nature and potential role of such factors in IFN-γR signaling is discussed.