Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1073/pnas.1207896109

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

11/12/2012

Volume

109

Pages

E3483 - E3492

Keywords

Amino Acid Sequence, Antigen-Presenting Cells, Crystallography, X-Ray, Epitopes, T-Lymphocyte, Genes, MHC Class I, HIV-1, HLA-B Antigens, Humans, Models, Molecular, Molecular Sequence Data, Polymorphism, Genetic, Protein Conformation, Receptors, Antigen, T-Cell, T-Lymphocytes, Thermodynamics