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Locus-Specific Constitutive and Cytokine-Induced HLA Class I Gene Expression ¹

Department of Pathology, Yale University School of Medicine, New Haven, CT 06510

Cytokine induction of the MHC class I genes increases the nascent molecules available for binding potentially antigenic peptides. The human H chain loci, HLA-A, -B, and -C, encode highly homologous and polymorphic mRNAs. Here, these transcripts were resolved and measured by competitive PCR of cDNA using locus-specific primers. Endothelial cells expressed many HLA-A and -B, but fewer HLA-C, transcripts. In contrast, HeLa cells expressed many HLA-A and -C, but fewer HLA-B, transcripts. The inflammatory cytokines TNF-, IFN-, and IFN- induced HLA-B strongly, but HLA-A and -C weakly in both cell types. Combined treatment with IFNs and TNF further increased HLA-A and -B, but not HLA-C transcripts. The constitutive and inducible activities of transfected promoters correlated well with mRNA levels. The weak IFN response of the HLA-A2 promoter was not due to variations in the IFN consensus sequence, the site , or a 3-bp insertion between them. The HLA-Cw6 promoter was less TNF responsive due to a variant B enhancer, which also reduced the IFN responses. The NF-B subunit RelA strongly activated the HLA-A2 and -B7 promoters but only weakly activated the HLA-Cw6 promoter due to the variant B. Cotransfecting NF-B1 with RelA further increased activity of the HLA-A2 and -B7, but not HLA-Cw6, promoters. All three promoters were activated by MHC class II trans-activator, but not CREB-binding protein, whereas IFN regulatory factor-1 and -2 weakly activated the HLA-B7 and -Cw6, but not HLA-A2, promoters. These studies illustrate common and locus-specific mechanisms that may be targeted to modulate immune reactions.

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