Structural basis of human β-cell killing by CD8⁺ T cells in Type 1 diabetes

Bulek, Anna M., Cole, David K., Skowera, Ania, Dolton, Garry, Gras, Stephanie, Madura, Florian, Fuller, Anna, Miles, John J., Gostick, Emma, Price, David A., Drijfhout, Jan W., Knight, Robin R., Huang, Guo C., Lissin, Nikolai, Molloy, Peter E., Wooldridge, Linda, Jakobsen, Bent K., Rossjohn, Jamie, Peakman, Mark, Rizkallah, Pierre J., and Sewell, Andrew K. (2012) Structural basis of human β-cell killing by CD8⁺ T cells in Type 1 diabetes. Nature Immunology, 13 (3). pp. 283-289.

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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.

Item ID: 45193
Item Type: Article (Refereed Research - C1)
Keywords: β-cell; crystal structure; peptide-major histocompatibility complex (pMHC); preproinsulin; surface plasmon resonance (SPR); T cell; T cell receptor (TCR); type 1 diabetes (T1D); vaccine
ISSN: 1529-2916
Funders: Biotechnology and Biological Sciences Research Council (BBSRC), Wellcome Trust (WT), Juvenile Diabetes Research Foundation (JDRF), European Union Seventh Framework Programme (EU FP7), National Institute for Health Research Biomedical Research Centre (NIHRBRC), Research Councils UK (RCUK), National Health and Medical Research Council (NHMRC), Wales Office of Research and Development (WORD), Medical Research Council (MRC)
Projects and Grants: BBSRC BB/H001085/1, WT WT086716, WT WT079848, WT WT095767, JDRF 7-2005-877, JDRF 1-2007-1803, JDRF 17-2009-806, EU FP7 241447 NAIMIT
Date Deposited: 17 Aug 2016 05:31
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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