title: Naturally processed non-canonical HLA-A*02:01 presented peptides.
abstract: Human leukocyte antigen (HLA) class I molecules generally present peptides (p) of 8 to 11 amino acids (aa) in length. Although an increasing number of examples with lengthy (>11 aa) peptides, presented mostly by HLA-B alleles, have been reported. Here we characterize HLA-A*02:01 restricted, in addition to the HLA-B*0702 and HLA-B*4402 restricted, lengthy peptides (>11 aa) arising from the B-cell ligandome. We analyzed a number of 15-mer peptides presented by HLA-A*02:01, and confirmed pHLA-I formation by HLA folding and thermal stability assays. Surprisingly the binding affinity and stability of the 15-mer epitopes in complex with HLA-A*02:01 were comparable with the values observed for canonical length (8 to 11 aa) HLA-A*02:01-restricted peptides. We solved the structures of two 15-mer epitopes in complex with HLA-A*02:01, within which the peptides adopted distinct super-bulged conformations. Moreover, we demonstrate that T-cells can recognize the 15-mer peptides in the context of HLA-A*02:01, indicating that these 15-mer peptides represent immunogenic ligands. Collectively, our data expand our understanding of longer epitopes in the context of HLA-I, highlighting that they are not limited to the HLA-B family, but can bind the ubiquitous HLA-A*02:01 molecule, and play an important role in T-cell immunity.
authors.affiliation: From the Departments of Immunohematology and Blood Transfusion and.
authors.forename: Chopie
authors.initials: C
authors.lastname: Hassan
authors.affiliation: the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton 3800, Australia.
authors.forename: Eric
authors.initials: E
authors.lastname: Chabrol
authors.affiliation: Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Jahn
authors.affiliation: Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Michel G D
authors.initials: MG
authors.lastname: Kester
authors.affiliation: From the Departments of Immunohematology and Blood Transfusion and.
authors.forename: Arnoud H
authors.initials: AH
authors.lastname: de Ru
authors.affiliation: From the Departments of Immunohematology and Blood Transfusion and.
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.affiliation: the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton 3800, Australia, the ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton 3800, Australia, and the Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, Wales, United Kingdom.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.affiliation: Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
authors.affiliation: Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Mirjam H M
authors.initials: MH
authors.lastname: Heemskerk
authors.affiliation: the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton 3800, Australia, the ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton 3800, Australia, and stephanie.gras@monash.edu.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gras
authors.affiliation: From the Departments of Immunohematology and Blood Transfusion and p.a.van_veelen@lumc.nl.
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
mesh_terms: D002460:Cell Line; D018360:Crystallography, X-Ray; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000737:chemistry* / Q000276:immunology; D015793:HLA-B7 Antigen / Q000737:chemistry / Q000276:immunology; D006801:Humans; D013058:Mass Spectrometry; D010455:Peptides; D011487:Protein Conformation
chemical_list: D018984:Epitopes, T-Lymphocyte; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; C477444:HLA-B*07:02 antigen; D015793:HLA-B7 Antigen; D010455:Peptides
keywords: Crystallography; HLA-A*02:01; Human Leukocyte Antigen Class I; Immunology; Mass Spectrometry (MS); Peptide Conformation; Peptides; Peptidomics; T-cell Immunity