Structural features underlying T-cell receptor sensitivity to concealed MHC class I micropolymorphisms
- PMID: 23161907
- PMCID: PMC3528510
- DOI: 10.1073/pnas.1207896109
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.
Conflict of interest statement
The authors declare no conflict of interest.
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References
-
- Kaslow RA, et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat Med. 1996;2(4):405–411. - PubMed
-
- Carrington M, et al. HLA and HIV-1: Heterozygote advantage and B*35-Cw*04 disadvantage. Science. 1999;283(5408):1748–1752. - PubMed
-
- Messaoudi I, Guevara Patiño JA, Dyall R, LeMaoult J, Nikolich-Zugich J. Direct link between mhc polymorphism, T cell avidity, and diversity in immune defense. Science. 2002;298(5599):1797–1800. - PubMed
-
- Hülsmeyer M, et al. HLA-B27 subtypes differentially associated with disease exhibit subtle structural alterations. J Biol Chem. 2002;277(49):47844–47853. - PubMed
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