Differential regulation of HLA-A3 and HLA-B7 MHC class I genes by IFN is due to two nucleotide differences in their IFN response sequences.

The transcription of HLA-A3 and HLA-B7 class I genes is differentially regulated by IFN-alpha and -gamma, the latter gene being more inducible than the former. To determine the structural basis of this differential response, hybrid genes were constructed in which complete or fragmented HLA-A3 or HLA-B7 promoters were fused to the chloramphenicol acetyl transferase coding sequence. These constructs were tested in transient transfection assays, and the differential response of the HLA-A3 and HLA-B7 genes to IFN was correlated with nucleotide differences in their interferon response sequences (IRS). Replacement of two T nucleotides in the HLA-A3 IRS by the homologous A and C nucleotides of the HLA-B7 IRS was sufficient to impart IFN inducibility of the HLA-A3 promoter and efficient binding of constitutive and IFN-induced nuclear factors to the IRS of HLA-A3. Since the same two nucleotide differences are shared by all sequenced HLA-A and HLA-B genes, these results suggest that high or low responsiveness to IFN might be a locus-related property.