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

Article Authors:Anna M Bulek; 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
Article Title:Structural basis for the killing of human beta cells by CD8(+) T cells in type 1 diabetes.
Reference Detail
Reference ID:1022868
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.
Affiliations:Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.
Reference Type:Literature
PubMed ID:22245737
Journal:Nat Immunol
Journal Volume:13
Article Pages:283-9
Journal ISSN:1529-2908
Article Chemical List:Histocompatibility Antigens;Receptors, Antigen, T-Cell
Article MeSH List:Apoptosis; CD8-Positive T-Lymphocytes(chemistry; immunology); Diabetes Mellitus, Type 1(immunology); Histocompatibility Antigens(immunology); Humans; Insulin-Secreting Cells(immunology; pathology); Models, Molecular; Protein Structure, Tertiary; Receptors, Antigen, T-Cell(chemistry; immunology)
Curation Last Updated:2015-06-05 03:24:38