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

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 RizkallahAndrew K Sewell

Research output: Contribution to journalArticle (Academic Journal)peer-review

119 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)283-9
Number of pages7
JournalNature Immunology
Volume13
Issue number3
DOIs
Publication statusPublished - Mar 2012

Keywords

  • Apoptosis
  • CD8-Positive T-Lymphocytes
  • Diabetes Mellitus, Type 1
  • Histocompatibility Antigens
  • Humans
  • Insulin-Secreting Cells
  • Models, Molecular
  • Protein Structure, Tertiary
  • Receptors, Antigen, T-Cell

Fingerprint Dive into the research topics of 'Structural basis for the killing of human beta cells by CD8(+) T cells in type 1 diabetes'. Together they form a unique fingerprint.

Cite this