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

Bulek, Anna, Cole, David ORCID:, Skowera, Ania, Dolton, Garry, Gras, Stephanie, Madura, Florian, Fuller, Anna, Miles, John, 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 ORCID:, Peakman, Mark, Rizkallah, Pierre ORCID: and Sewell, Andrew 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 autoreactive-T cell receptor (TCR) engagement of major histocompatability (MHC) class II-restricted self-antigens is established, but how autoimmune- TCRs interact with self-MHC class I has been unclear. We examined how CD8+ T cells kill human islet β-cells, in Type-1 diabetes, via autoreactive-TCR (1E6) recognition of an HLAA* 0201-restricted glucose-sensitive preproinsulin peptide. Rigid ‘lock-and-key’ binding underpinned the 1E6-HLA-A*0201-peptide interaction, whereby 1E6 docked similarly to most MHCI-restricted TCRs. However, this interaction was extraordinarily weak, due to limited contacts with MHCI. TCR binding was highly peptide-centric, dominated by two CDR3-loopencoded residues, acting as an ‘aromatic-cap’, over the peptide MHCI (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
Subjects: R Medicine > R Medicine (General)
Publisher: Nature Publishing Group
ISSN: 1529-2908
Date of First Compliant Deposit: 4 October 2017
Date of Acceptance: 6 December 2011
Last Modified: 03 Nov 2022 09:31

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