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Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity

Cole, David, Bulek, Anna Marta, Dolton, Garry Michael, Schauenberg, Andrea J., Szomolay, Barbara, Rittase, William, Trimby, Andrew, Jothikumar, Prithiviraj, Fuller, Anna, Skowera, Ania, Rossjohn, Jamie, Zhu, Cheng, Miles, John J., Peakman, Mark, Wooldridge, Linda, Rizkallah, Pierre and Sewell, Andrew K. 2016. Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity. The Journal of Clinical Investigation 126 (6) , pp. 2191-2204. 10.1172/JCI85679

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Abstract

The cross-reactivity of T cells with pathogen- and self-derived peptides has been implicated as a pathway involved in the development of autoimmunity. However, the mechanisms that allow the clonal T cell antigen receptor (TCR) to functionally engage multiple peptide–major histocompatibility complexes (pMHC) are unclear. Here, we studied multiligand discrimination by a human, preproinsulin reactive, MHC class-I–restricted CD8+ T cell clone (1E6) that can recognize over 1 million different peptides. We generated high-resolution structures of the 1E6 TCR bound to 7 altered peptide ligands, including a pathogen-derived peptide that was an order of magnitude more potent than the natural self-peptide. Evaluation of these structures demonstrated that binding was stabilized through a conserved lock-and-key–like minimal binding footprint that enables 1E6 TCR to tolerate vast numbers of substitutions outside of this so-called hotspot. Highly potent antigens of the 1E6 TCR engaged with a strong antipathogen-like binding affinity; this engagement was governed though an energetic switch from an enthalpically to entropically driven interaction compared with the natural autoimmune ligand. Together, these data highlight how T cell cross-reactivity with pathogen-derived antigens might break self-tolerance to induce autoimmune disease.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QR Microbiology > QR180 Immunology
Publisher: American Society for Clinical Investigation
ISSN: 0021-9738
Funders: Wellcome Trust, BBSRC
Date of First Compliant Deposit: 23 May 2016
Date of Acceptance: 10 March 2016
Last Modified: 24 May 2019 20:28
URI: http://orca-mwe.cf.ac.uk/id/eprint/91149

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