We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Structural basis for the killing of human beta cells by CD8<sup>+</sup> T cells in type 1 diabetes.
- Authors
Bulek, Anna M; Cole, David K; Skowera, Ania; Dolton, Garry; Gras, Stephanie; Madura, Florian; Fuller, Anna; Miles, John J; Gostick, Emma; Price, David A; 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 J
- 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.
- Subjects
PANCREATIC beta cells; T cells; TYPE 1 diabetes; MAJOR histocompatibility complex; ANTIGEN receptors; LEUCOCYTES; PEPTIDES
- Publication
Nature Immunology, 2012, Vol 13, Issue 3, p283
- ISSN
1529-2908
- Publication type
Article
- DOI
10.1038/ni.2206