Bulek, Anna, Cole, David  ORCID: https://orcid.org/0000-0003-0028-9396, Skowera, Ania, Dolton, Garry, Gras, Stephanie, Madura, Florian, Fuller, Anna, Miles, John, Gostick, Emma, Price, David ORCID: https://orcid.org/0000-0001-9416-2737, Drijfhout, Jan W, Knight, Robin R, Huang, Guo C, Lissin, Nikolai, Molloy, Peter E, Wooldridge, Linda, Jakobsen, Bent K, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Peakman, Mark, Rizkallah, Pierre ORCID: https://orcid.org/0000-0002-9290-0369 and Sewell, Andrew ORCID: https://orcid.org/0000-0003-3194-3135
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
|
Abstract
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: | 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: | 10 Jun 2023 01:07 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/105168 |
Citation Data
Cited 127 times in Scopus. View in Scopus. Powered By Scopus® Data
Actions (repository staff only)
 |
Edit Item |
Dimensions
Dimensions