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

Nat Immunol. 2012 Jan 15;13(3):283-9. doi: 10.1038/ni.2206.

Anna M Bulek ¹, David K Cole, Ania Skowera, Garry Dolton, Stephanie Gras, Florian Madura, Anna Fuller, John J Miles, Emma Gostick, David A Price, Jan W Drijfhout, Robin R Knight, Guo C Huang, Nikolai Lissin, Peter E Molloy, Linda Wooldridge, Bent K Jakobsen, Jamie Rossjohn, Mark Peakman, Pierre J Rizkallah, Andrew K Sewell

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Affiliation

1 Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.

PMID: 22245737 DOI: 10.1038/ni.2206

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.

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