Structural features underlying T-cell receptor sensitivity to concealed MHC class I micropolymorphisms.
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 un...
Main Authors: | , , , , , , , |
---|---|
Format: | Journal article |
Language: | English |
Published: |
2012
|
_version_ | 1797053562153336832 |
---|---|
author | Stewart-Jones, G Simpson, P Van Der Merwe, P Easterbrook, P Mcmichael, A Rowland-Jones, S Jones, E Gillespie, G |
author_facet | Stewart-Jones, G Simpson, P Van Der Merwe, P Easterbrook, P Mcmichael, A Rowland-Jones, S Jones, E Gillespie, G |
author_sort | Stewart-Jones, G |
collection | OXFORD |
description | 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. |
first_indexed | 2024-03-06T18:45:24Z |
format | Journal article |
id | oxford-uuid:0e557988-d491-4028-86ee-72ba8fa62f36 |
institution | University of Oxford |
language | English |
last_indexed | 2024-03-06T18:45:24Z |
publishDate | 2012 |
record_format | dspace |
spelling | oxford-uuid:0e557988-d491-4028-86ee-72ba8fa62f362022-03-26T09:45:21ZStructural features underlying T-cell receptor sensitivity to concealed MHC class I micropolymorphisms.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0e557988-d491-4028-86ee-72ba8fa62f36EnglishSymplectic Elements at Oxford2012Stewart-Jones, GSimpson, PVan Der Merwe, PEasterbrook, PMcmichael, ARowland-Jones, SJones, EGillespie, GPolymorphic 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. |
spellingShingle | Stewart-Jones, G Simpson, P Van Der Merwe, P Easterbrook, P Mcmichael, A Rowland-Jones, S Jones, E Gillespie, G Structural features underlying T-cell receptor sensitivity to concealed MHC class I micropolymorphisms. |
title | Structural features underlying T-cell receptor sensitivity to concealed MHC class I micropolymorphisms. |
title_full | Structural features underlying T-cell receptor sensitivity to concealed MHC class I micropolymorphisms. |
title_fullStr | Structural features underlying T-cell receptor sensitivity to concealed MHC class I micropolymorphisms. |
title_full_unstemmed | Structural features underlying T-cell receptor sensitivity to concealed MHC class I micropolymorphisms. |
title_short | Structural features underlying T-cell receptor sensitivity to concealed MHC class I micropolymorphisms. |
title_sort | structural features underlying t cell receptor sensitivity to concealed mhc class i micropolymorphisms |
work_keys_str_mv | AT stewartjonesg structuralfeaturesunderlyingtcellreceptorsensitivitytoconcealedmhcclassimicropolymorphisms AT simpsonp structuralfeaturesunderlyingtcellreceptorsensitivitytoconcealedmhcclassimicropolymorphisms AT vandermerwep structuralfeaturesunderlyingtcellreceptorsensitivitytoconcealedmhcclassimicropolymorphisms AT easterbrookp structuralfeaturesunderlyingtcellreceptorsensitivitytoconcealedmhcclassimicropolymorphisms AT mcmichaela structuralfeaturesunderlyingtcellreceptorsensitivitytoconcealedmhcclassimicropolymorphisms AT rowlandjoness structuralfeaturesunderlyingtcellreceptorsensitivitytoconcealedmhcclassimicropolymorphisms AT jonese structuralfeaturesunderlyingtcellreceptorsensitivitytoconcealedmhcclassimicropolymorphisms AT gillespieg structuralfeaturesunderlyingtcellreceptorsensitivitytoconcealedmhcclassimicropolymorphisms |