NDLI: Structural features underlying T-cell receptor sensitivity to concealed MHC class I micropolymorphisms

Content Provider	PubMed Central
Author	Stewart-jones, Guillaume B. Simpson, Peter Merwe, P. Anton Van Der Easterbrook, Philippa Mcmichael, Andrew J. Rowland-jones, Sarah L. Jones, E. Yvonne Gillespie, Geraldine M.
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-B5701 but is not selected by HLA-B5703, which differs from HLA-B5701 by two concealed polymorphisms. Our findings illustrate that although both HLA-B57 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.
Related Links	http://dx.doi.org/10.1073/pnas.1207896109
Starting Page	3483
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	50
Volume Number	109
Language	English
Publisher	National Academy of Sciences
Publisher Date	2012-12-11
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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Structural features underlying T-cell receptor sensitivity to concealed MHC class I micropolymorphisms.

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