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

Cole, David K. ORCID: https://orcid.org/0000-0003-0028-9396, Bulek, Anna M., Dolton, Garry, Schauenberg, Andrea J., Szomolay, Barbara ORCID: https://orcid.org/0000-0002-5375-5533, Rittase, William, Trimby, Andrew, Jothikumar, Prithiviraj, Fuller, Anna, Skowera, Ania, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Zhu, Cheng, Miles, John J., Peakman, Mark, Wooldridge, Linda, Rizkallah, Pierre J. ORCID: https://orcid.org/0000-0002-9290-0369 and Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135 2016. Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity. 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
Additional Information:	This work is licensed under the Creative Commons Attribution 4.0 International License
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:	18 Mar 2024 07:31
URI:	https://orca.cardiff.ac.uk/id/eprint/91149

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