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| Article Authors: | Anna M Bulek; David K Cole; Ania Skowera; Garry Dolton; Stephanie Gras; Florian Madura; Anna Fuller; John J Miles; Emma Gostick; David A Price; Jan W Drijfhout; Robin R Knight; Guo C Huang; Nikolai Lissin; Peter E Molloy; Linda Wooldridge; Bent K Jakobsen; Jamie Rossjohn; Mark Peakman; Pierre J Rizkallah; Andrew K Sewell |
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| Article Title: | Structural basis for the killing of human beta cells by CD8(+) T cells in type 1 diabetes. |
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| Reference ID: | 1022868 |
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| Abstract: | The structural characteristics of the engagement of major histocompatibility complex (MHC) class II-restricted self antigens by autoreactive T cell antigen receptors (TCRs) is established, but how autoimmune TCRs interact with complexes of self peptide and MHC class I has been unclear. Here we examined how CD8(+) T cells kill human islet beta cells in type 1 diabetes via recognition of a human leukocyte antigen HLA-A*0201-restricted glucose-sensitive preproinsulin peptide by the autoreactive TCR 1E6. Rigid 'lock-and-key' binding underpinned the 1E6-HLA-A*0201-peptide interaction, whereby 1E6 docked similarly to most MHC class I-restricted TCRs. However, this interaction was extraordinarily weak because of limited contacts with MHC class I. TCR binding was highly peptide centric, dominated by two residues of the complementarity-determining region 3 (CDR3) loops that acted as an 'aromatic-cap' over the complex of peptide and MHC class I (pMHCI). Thus, highly focused peptide-centric interactions associated with suboptimal TCR-pMHCI binding affinities might lead to thymic escape and potential CD8(+) T cell-mediated autoreactivity. |
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| Affiliations: | 1] Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK. [2]. |
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| Date: | 2012 |
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| Reference Type: | Literature |
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| PubMed ID: | 22245737 |
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| Journal: | Nat Immunol |
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| Journal Volume: | 13 |
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| Article Pages: | 283-9 |
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| Journal ISSN: | 1529-2916 |
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| Curation Last Updated: | 2012-09-26 20:01:04 |
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