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

DOI: 10.1038/ni.2206 DOI Help
PMID: 22245737 PMID Help

Authors: Anna Bulek (Cardiff University) , David Cole (Cardiff University) , Ania Skowera (King's College London) , Garry Dolton (Cardiff University School of Medicine) , Stephanie Gras (Monash University) , Florian Madura (Cardiff University) , Anna Fuller (Cardiff University) , John Miles (Cardiff University) , Emma Gostick (Cardiff University) , David A. Price (Cardiff University School of Medicine) , Jan W. Drijfhout (University Medical Centre) , Robin R. Knight (King's College London) , Guo C. Huang (King's College London) , Nikolai Lissin (Immunocore) , Peter E. Molloy (Immunocore) , Linda Fothergill-gilmore (University of Edinburgh) , Bent K. Jakobsen (King's College London, London) , Jamie Rossjohn (Monash University) , Mark Peakman (Guy's & St. Thomas' National Health Service Foundation Trust and King's College London) , Pierre Rizkallah (Cardiff University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Immunology

State: Published (Approved)
Published: January 2012

Open Access Open Access

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.

Journal Keywords: CD8-Positive; Diabetes; Type; Histocompatibility; Humans; Insulin-Secreting; Models; Molecular; Protein; Tertiary; Receptors; Antigen; T-Cell

Subject Areas: Biology and Bio-materials

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)