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Structural basis for the killing of human beta cells by CD8+ T cells in type 1 diabetes

Bulek, Anna Marta, Cole, David ORCID:, Skowera, Ania, Dolton, Garry Michael, Gras, Stephanie, Madura, Florian, Fuller, Anna, Miles, John James, Gostick, Emma, Price, David ORCID:, Drijfhout, Jan W., Knight, Robin R., Huang, Guo C., Lissin, Nikolai, Molloy, Peter E., Wooldridge, Linda, Jakobsen, Bent K., Rossjohn, Jamie, Peakman, Mark, Rizkallah, Pierre ORCID: and Sewell, Andrew K. ORCID: 2012. Structural basis for the killing of human beta cells by CD8+ T cells in type 1 diabetes. Nature Immunology 13 (3) , pp. 283-289. 10.1038/ni.2206

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RC Internal medicine
Publisher: Nature Publishing Group
ISSN: 1529-2908
Last Modified: 10 Jun 2023 01:09

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