title: Structural features underlying T-cell receptor sensitivity to concealed MHC class I micropolymorphisms.
abstract: Polymorphic differences distinguishing MHC class I subtypes often permit the presentation of shared epitopes in conformationally identical formats but can affect T-cell repertoire selection, differentially impacting autoimmune susceptibilities and viral clearance in vivo. The molecular mechanisms underlying this effect are not well understood. We performed structural, thermodynamic, and functional analyses of a conserved T-cell receptor (TCR) which is frequently expanded in response to a HIV-1 epitope when presented by HLA-B*5701 but is not selected by HLA-B*5703, which differs from HLA-B*5701 by two concealed polymorphisms. Our findings illustrate that although both HLA-B*57 subtypes display the epitope in structurally conserved formats, the impact of their polymorphic differences occurs directly as a consequence of TCR ligation, primarily because of peptide adjustments required for TCR binding, which involves the interplay of polymorphic residues and water molecules. These minor differences culminate in subtype-specific differential TCR-binding kinetics and cellular function. Our data demonstrate a potential mechanism whereby the most subtle MHC class I micropolymorphisms can influence TCR use and highlight their implications for disease outcomes.
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital,  University of Oxford, Oxford OX3 9DS,  United Kingdom.
authors.forename: Guillaume B
authors.initials: GB
authors.lastname: Stewart-Jones
authors.forename: Peter
authors.initials: P
authors.lastname: Simpson
authors.forename: P Anton
authors.initials: PA
authors.lastname: van der Merwe
authors.forename: Philippa
authors.initials: P
authors.lastname: Easterbrook
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McMichael
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Rowland-Jones
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
authors.forename: Geraldine M
authors.initials: GM
authors.lastname: Gillespie
mesh_terms: D000595:Amino Acid Sequence; D000938:Antigen-Presenting Cells / Q000276:immunology; D018360:Crystallography, X-Ray; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005805:Genes, MHC Class I; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D015235:HLA-B Antigens / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D013816:Thermodynamics
chemical_list: D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; C484830:HLA-B*57:01 antigen; C103707:HLA-B57 antigen; D011948:Receptors, Antigen, T-Cell