Journal
NATURE IMMUNOLOGY
Volume 13, Issue 3, Pages 283-U1521Publisher
NATURE PORTFOLIO
DOI: 10.1038/ni.2206
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Funding
- Biotechnology and Biological Sciences Research Council [BB/H001085/1]
- Wellcome Trust [WT086716, WT079848, WT095767]
- Juvenile Diabetes Research Foundation [7-2005-877, 1-20071803, 17-2009-806]
- European Union [241447]
- National Institute for Health Research Comprehensive Biomedical Research Center at Guy's & St. Thomas' National Health Service Foundation Trust
- King's College London, Research Councils UK
- National Health and Medical Research Council
- Welsh Office of Research and Development
- Medical Research Council
- BBSRC [BB/H001085/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H001085/1] Funding Source: researchfish
- Medical Research Council [MR/J006742/1] Funding Source: researchfish
- Tenovus Cancer Care [PhD2009/L20] Funding Source: researchfish
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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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