title: High resolution structures of highly bulged viral epitopes bound to major histocompatibility complex class I. Implications for T-cell receptor engagement and T-cell immunodominance.
abstract: Although HLA class I alleles can bind epitopes up to 14 amino acids in length, little is known about the immunogenicity or the responding T-cell repertoire against such determinants. Here, we describe an HLA-B*3508-restricted cytotoxic T lymphocyte response to a 13-mer viral epitope (LPEPLPQGQLTAY). The rigid, centrally bulged epitope generated a biased T-cell response. Only the N-terminal face of the peptide bulge was critical for recognition by the dominant clonotype SB27. The SB27 public T-cell receptor (TcR) associated slowly onto the complex between the bulged peptide and the major histocompatibility complex, suggesting significant remodeling upon engagement. The broad antigen-binding cleft of HLA-B*3508 represents a critical feature for engagement of the public TcR, as the narrower binding cleft of HLA-B*3501(LPEPLPQGQLTAY), which differs from HLA-B*3508 by a single amino acid polymorphism (Arg156 --> Leu), interacted poorly with the dominant TcR. Biased TcR usage in this cytotoxic T lymphocyte response appears to reflect a dominant role of the prominent peptide x major histocompatibility complex class I surface.
authors.affiliation: Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Fleur E
authors.initials: FE
authors.lastname: Tynan
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Borg
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.forename: Travis
authors.initials: T
authors.lastname: Beddoe
authors.forename: Diah
authors.initials: D
authors.lastname: El-Hassen
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Silins
authors.forename: Wendy J M
authors.initials: WJ
authors.lastname: van Zuylen
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.forename: Lars
authors.initials: L
authors.lastname: Kjer-Nielsen
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burrows
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell