Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 50, Pages E3483-E3492Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1207896109
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Funding
- MRC [MR/J002011/1, G9900061, G0501011] Funding Source: UKRI
- Medical Research Council [G0501011, G9722488, G1000800f, MR/J002011/1, G9900061, G19/31] Funding Source: researchfish
- Medical Research Council [MR/J002011/1, G0501011, G9900061, G9722488, G19/31] Funding Source: Medline
- Wellcome Trust [090532] Funding Source: Medline
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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.
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