Structural basis of human beta-cell killing by CD8+ T cells in Type 1 diabetes
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1
Cardiff University, United Kingdom
Authors and affiliations:
David K. Cole1*, Anna M. Bulek1*, , Ania Skowera2,3*, Garry Dolton1, Stephanie Gras4, Florian Madura1, Anna Fuller1, John J. Miles1, Emma Gostick1, David A. Price1, Jan W. Drijfhout6, Robin R. Knight2, Guo C. Huang7, Nikolai Lissin5, Peter E. Molloy5, Linda Wooldridge1, Bent K. Jakobsen5, Jamie Rossjohn1,4, Mark Peakman2,3*, Pierre J. Rizkallah1* and Andrew K. Sewell1*
1Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK; 2Department of Immunobiology, King's College London, London, UK; 3NIHR Biomedical Research Centre at Guy’s & St Thomas’ NHS Foundation Trust and King’s College London, London, UK; 4The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia; 5Immunocore Ltd., 57c Milton Park, Abingdon, UK; 6Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, Netherlands. 7Diabetes and Nutritional Science King's College London, London, UK
This study has been recently published in Nature Immunology (Nature Immunology. 2012 Jan 15;13(3):283-9) and was featured in the News and Views section of the same issue. Furthermore, it was voted in the top 2% of all biomedical publications in FS1000 and has generated broad media interest (TV, radio and internet).
Abstract:
Structural basis of human beta-cell killing by CD8+ T cells in Type 1 diabetes
Autoreactive T-cells are thought to play a role in type 1 diabetes (T1D) by potentially killing insulin producing beta cells in the pancreas, although the mechanism has not been fully resolved. The antigen specific interaction between the T-cell receptor (TCR), on the T-cell surface, and peptide-major histocompatibility complexes (pMHCs) on the target cell surface, govern T-cell mediated immunity. Thus, we examined how T-cells kill human islet beta cells by solving the atomic structure of an autoreactive-TCR (1E6) specific for a MHC-restricted glucose-sensitive preproinsulin peptide (A2-ALW).
Rigid ‘lock-and-key’ binding underpinned the 1E6-A2-ALW interaction, whereby 1E6 docked similarly to most MHCI-restricted TCRs. However, this interaction was extraordinarily weak, due to limited contacts with MHCI. Thus, highly focused peptide-centric interactions associated with suboptimal TCR-pMHCI binding affinities might lead to thymic escape and potential T-cell-mediated autoreactivity.
This first sight of how T-cells target insulin producing beta cells has increased our understanding of how T1D arises. This knowledge will be used in the future to help predict who might get the disease, and also to develop new approaches to prevent it. Our aim is to catch the disease early before too many insulin-producing beta cells have been damaged.
Keywords:
type 1 diabetes,
T cell receptor,
Structure,
Surface Plasmon Resonance,
Autoimmunity,
Major Histocompatibility Complex
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Immune receptors and signaling
Citation:
Cole
DK
(2013). Structural basis of human beta-cell killing by CD8+ T cells in Type 1 diabetes
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Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00206
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Received:
14 Mar 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. David K Cole, Cardiff University, Cardiff, United Kingdom, coledk@cf.ac.uk