FUNCTIONAL-CHARACTERIZATION OF A HYBRID HUMAN MOUSE INTERFERON-GAMMA RECEPTOR - EVIDENCE FOR SPECIES-SPECIFIC INTERACTION OF THE EXTRACELLULAR RECEPTOR DOMAIN WITH A PUTATIVE SIGNAL TRANSDUCER

The human interferon gamma (IFN-gamma) receptor expressed in mouse cel ls displays binding properties indistinguishable from those of the res ident receptor on human cells. Still, mouse cells expressing the human IFN-gamma receptor remain insensitive to human IFN-gamma. It is widel y accepted that at least one species-specific cofactor encoded within human chromosome 21 is required for signal transduction. To define str uctural domains of the human IFN-gamma receptor responsible for this s pecies-specific interaction, a hybrid between the human and the murine receptor was constructed and expressed in mouse L929 cells or in mous e L cell-derived SCC16-5 cells, which contain human chromosome 21. Thi s hybrid receptor, which consisted of the extracellular domain of the human IFN-gamma receptor and the transmembrane and cytoplasmic domains of the murine IFN-gamma receptor, was found to bind human IFN-gamma w ith high affinity. However, only SCC16-5 cells expressing the human/mo use hybrid receptor were responsive to human IFN-gamma as revealed by enhanced expression of major histocompatibility complex class I antige ns, induction of the transcription factor IRF-1, and induction of a pa rtial antiviral state. These findings strongly suggest that IFN-gamma- mediated signal transduction requires a species-specific interaction o f the extracellular portion of the known ligand-binding IFN-gamma rece ptor chain with an additional, presumably membrane-anchored receptor s ubunit.