Identification of an elaborate NK-specific system regulating HLA-C expression

• DOI: 10.1371/journal.pgen.1007163
• Publication Date: 2018-01-12T18:25:22Z
• Authors: Hongchuan Li; Martin A. Ivarsson; Victoria E. Walke...; Jeff Subleski; Jenna K. Johnson; Paul W. Wright; Mary Carrington; Niklas K. Björkström; Daniel W. McVicar; Stephen K. Anderson
• Keywords: Cell biology; Blood cells; 570; Physiology; Immunology; MHC class I genes; Genes, MHC Class I; NK cells; HLA-C Antigens; QH426-470; Lymphocyte Activation; Biochemistry; Cell Degranulation; Major Histocompatibility Complex; 03 medical and health sciences; 0302 clinical medicine; Immune Physiology; Cellular types; Genetics; Humans; Molecular Biology Techniques; Molecular Biology; Alleles; Cells, Cultured; Medicine and health sciences; Biology and life sciences; Messenger RNA; Immune cells; Cell Differentiation; 3. Good health; Nucleic acids; Killer Cells, Natural; Gene types; Animal cells; Gene Expression Regulation; Genetic Loci; White blood cells; RNA; Clinical Immunology; Clinical Medicine; Spleen; Cloning; Developmental Biology; Research Article; HeLa Cells

The HLA-C gene appears to have evolved in higher primates to serve as a dominant source of ligands for the KIR2D family of inhibitory MHC class I receptors. The expression of NK cell-intrinsic MHC class I has been shown to regulate the murine Ly49 family of MHC class I receptors due to the interaction of these receptors with NK cell MHC in cis. However, cis interactions have not been demonstrated for the human KIR and HLA proteins. We report the discovery of an elaborate NK cell-specific system regulating HLA-C expression, indicating an important role for HLA-C in the development and function of NK cells. A large array of alternative transcripts with differences in intron/exon content are generated from an upstream NK-specific HLA-C promoter, and exon content varies between HLA-C alleles due to SNPs in splice donor/acceptor sites. Skipping of the first coding exon of HLA-C generates a subset of untranslatable mRNAs, and the proportion of untranslatable HLA-C mRNA decreases as NK cells mature, correlating with increased protein expression by mature NK cells. Polymorphism in a key Ets-binding site of the NK promoter has generated HLA-C alleles that lack significant promoter activity, resulting in reduced HLA-C expression and increased functional activity. The NK-intrinsic regulation of HLA-C thus represents a novel mechanism controlling the lytic activity of NK cells during development.