DISSECTION OF THE INTERFERON-GAMMA-MHC CLASS-II SIGNAL TRANSDUCTION PATHWAY REVEALS THAT TYPE-I AND TYPE-II INTERFERON SYSTEMS SHARE COMMON SIGNALING COMPONENT(S)

We have used a herpes virus thymidine kinase (HSV-TK) based metabolic selection system to isolate mutants defective in the interferon-gamma mediated induction of the MHC class II promoter. All the mutations act in trans and result in no detectable induction of MHC and invariant chain (Ii) gene expression. Scatchard analysis indicates that the mutants have a normal number of surface IFN-gamma receptors with the same affinity constant. The mutants fall into two broad categories. One class of mutants is still able to induce MHC class I, IRF-1, 9-27, 1-8 and GBP genes by IFN-gamma. A second class of mutants is defective for the IFN-gamma induction of all the genes tested; surprisingly, the IFN-alpha/beta induction of MHC class I, 9-27, ISG54 and ISG15 genes is also defective in these mutants, although different members of this class can be discriminated by the response of the GBP and IRF-1 genes to type I interferons. These data demonstrate that the signalling pathways of both type I and type II interferon systems share common signal transduction component(s). These mutants will be useful for the study of IFN-gamma regulation of class II genes and Ii chain, and to elucidate molecular components of type I and type II interferon signal transduction.