title: The diversity of the HLA-E-restricted peptide repertoire explains the immunological impact of the Arg107Gly mismatch.
abstract: Human leukocyte antigen (HLA)-E molecules are potent inhibitors of NK cell-mediated killing. Low in polymorphisms, two alleles are widely expressed among diverse populations: HLA-E*01:01 and HLA-E*01:03. Both alleles are distinguished by one SNP resulting in the substitution Arg107Gly. Both alleles present a limited set of peptides derived from class I leader sequences physiologically; however, HLA-E*01:01 presents non-canonical peptides in the absence of HLA class I molecules. To further assess the functional differences between both alleles, we analyzed the peptide repertoire of HLA-E*01:03 by applying soluble HLA technology followed by mass-spectrometric peptide sequencing. HLA-E*01:03 restricted peptides showed a length of 9-17 amino acids and differed in their biophysical properties, no overlap in the peptide repertoire of both allelic variants could be observed; however, both alleles shared marginal peptides from the same proteomic content. Artificial APCs expressing empty HLA-E*01:01 or E*01:03 molecules were generated and stabilized using cognate HLA class I-derived peptide ligands to analyze the impact of residue 107 within the HLA-E heavy chain on the NKG2/CD94 receptor engagement. Differences in peptide stabilization could be translated to the density and half-life time of peptide-HLA-E molecules on the cell surface that subsequently impacted NK cell inhibition as verified by cytotoxicity assays. Taken together, these data illustrate functional differences of HLA-E allelic variants induced by a single amino acid. Furthermore, the function of HLA-E in pathophysiologic situations when the HLA processing machinery is interrupted seems to be more emphasized than previously described, implying a crucial role for HLA-E in tumor or viral immune episodes.
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, Medical Park, Feodor-Lynen-Str. 5, 30625, Hannover, Germany.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Celik
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, Medical Park, Feodor-Lynen-Str. 5, 30625, Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kraemer
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, Medical Park, Feodor-Lynen-Str. 5, 30625, Hannover, Germany.
authors.forename: Trevor
authors.initials: T
authors.lastname: Huyton
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, Medical Park, Feodor-Lynen-Str. 5, 30625, Hannover, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Blasczyk
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, Medical Park, Feodor-Lynen-Str. 5, 30625, Hannover, Germany. bade-doeding.christina@mh-hannover.de.
authors.forename: Christina
authors.initials: C
authors.lastname: Bade-Döding
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine / Q000235:genetics; D002460:Cell Line; D003601:Cytotoxicity Tests, Immunologic; D005805:Genes, MHC Class I; D005998:Glycine / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D026901:Membrane Transport Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms; D021382:Protein Sorting Signals / Q000502:physiology; D000097625:HLA-E Antigens
chemical_list: D001120:Arginine; D005998:Glycine; D015395:Histocompatibility Antigens Class I; D026901:Membrane Transport Proteins; D010455:Peptides; D020033:Protein Isoforms; D021382:Protein Sorting Signals; D000097625:HLA-E Antigens; C107762:tapasin
keywords: Diverse HLA-E peptide repertoire; HLA-E*01:03; Non-canonical peptides; Tumor immune escape