The regulatory complex of HLA class I promoters exhibits locus-specific conservation with limited allelic variation.

Abstract

The extensive genetic polymorphism of the classical MHC class I molecules provides an important distinguishing feature of the host's immune system. They influence the selection and function of effector cells against tumor and virally infected cells. In these cells, class I molecules are often selectively suppressed. This suppression is locus specific and, in certain cases, allele specific. We analyzed the HLA class I promoter sequences that include class I regulatory complex (CRC) in a total of 41 well-characterized HLA homozygous B lymphoblastoid cell lines, using locus-specific oligonucleotide probes complementary to the overlapping CRC elements. These include kappa B1, kappa B2, IFN response sequence, the putative negative regulatory element, and the HLA counterpart of the H-2RII region that contains the retinoid x receptor beta binding motif. The CRC of HLA promoters displayed locus-specific conservation; however, limited allelic variation was observed in each of the cis elements. In some, variations were apparently generated by gene conversion. The palindromic kappa B1 site, which has an active role in enhancing promoter activity, was found to be conserved in almost all HLA-A and -B alleles, but not in HLA-C. The core DNA binding motif for retinoid x receptor beta was absent within the HLA CRC region. Sequence analysis of promoters from HLA-A31, -B13, and -Cw1 genomic clones, as well as pairwise interallelic and intra-allelic comparison with those of published alleles, showed that locus-specific conservation extended throughout the promoter sequences. Locus specificity and the allelic variation seen in the CRC regions may provide a structural basis for the selective modulation of HLA class I genes.