Transactivation of classical and nonclassical HLA class I genes through the IFN-stimulated response element

The IFN-stimulated response element (ISRE) is an important conserved cis-ac ting regulatory element in the promoter of MHC class I genes, but displays considerable locus-specific nucleotide variation. In this report, the putat ive ISREs of classical and nonclassical HLA class I genes were investigated for their contribution to MHC class I transactivation, It is shown that IF N-gamma induced MHC class I transactivation through the ISRE of HLA-A, HLA- B, HLA-C, and HLA-F, This is congruent with the binding of IFN regulatory f actor-1 to the ISREs of these loci upon IFN-gamma treatment. Spl was shown to bind to the CG-rich sequences in the ISRE regions of HLA-B, HLA-C, and H LA-G, The putative E box 5' of the ISRE in most HLA-B alleles was shown to bind the upstream stimulatory factors (USF) 1 and 2, The Sp1 and USF bindin g sites did not influence IFN-gamma-induced transactivation. However, the U SP binding site played a suppressive role in the constitutive expression of HLA-B, The locus-specific transcriptional control through the ISRE could b e an important mechanism in the differential regulation of classical and no nclassical MHC class I expression, which determines adequate Ag presentatio n upon pathogenic challenge.