At least two species-specific gene products are required for signal transduction by interferon gamma (IFN-y). The first is the IFN-y receptor, which binds ligand with high affinity in a species-specific manner. The second is an undetermined species-specific signal transducer(s). To determine whether the human IFN-y receptor (hIFN--yR) IFN-,y binds with high affinity (Kd = 10-9 to 10-11 M at 4°C) to a 90-kDa glycoprotein receptor present in low numbers (102 to 104) on a wide variety of cell types (7,16,19,33,36,42,51). Human and murine IFN-y share 40%o amino acid sequence identity (22) and exhibit species specificity with respect to receptor binding (15, 52) and biological activity (14,22). Human and murine IFN--y receptor (hIFN--yR and mIFN--yR, respectively) cDNAs have been cloned and expressed (2,12,23,25,32,39 affinity to the hIFN-yR but no biological response is elicited. The hIFN-yR as expressed in murine somatic cell hybrids and transfected mouse cells has binding properties similar to those of the hIFN--yR on human cells (1,7,36,42). These findings, in conjunction with results of cross-linking experiments (7,19,36,40), suggest that in contrast to the interleukin-6 (26, 54) and granulocyte-macrophage colony-stimulating factor receptors (21, 24), a second IFN--yR chain is not involved in mediating high-affinity ligand binding.Human-murine somatic cell hybrids containing human chromosomes 6 and 21 (29), as well as human-hamster and human-murine somatic cell hybrids containing human chromosome 21 and transfected with hIFN--yR expression vectors (17, 28), respond to hIFN-y as measured by the induction of MHC class I antigen. These findings demonstrate that the human chromosome 21-encoded factor(s) is necessary for signalling by the hIFN-yR, at least with respect to histocompatibility antigen expression, and suggest that the signal transducer(s) and the IFN-yR must be from the same species. How these two species-specific molecules function is unknown.To determine the region(s) of the IFN-yR that must be from the same species as the signal transducer to generate a functional response to IFN-y, we constructed expression vectors for human and hybrid human-murine IFN-y receptors. We transfected each expression vector into two different murine cell lines, one of which (SCC-16-5) contains a single copy of human chromosome 21. Transfectants were stimulated with hIFN-y and analyzed for increased expression of murine MHC class I antigen. Using this approach, we identified the region of the IFN--yR that cooperates with the species-specific signalling element(s).
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