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

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

Full text not available from this repository.

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:	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