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Identification of human viral protein-derived ligands recognized by individual MHCI-restricted T-cell receptors

Szomolay, Barbara, Liu, Jie, Brown, Paul E, Miles, John J, Clement, Mathew, Llewellyn-Lacey, Sian, Dolton, Garry, Ekeruche-Makinde, Julia, Lissina, Anya, Schauenburg, Andrea, Sewell, Andrew, Burrows, Scott R, Roederer, Mario, Price, David, Wooldridge, Linda and van den Berg, Hugo A 2016. Identification of human viral protein-derived ligands recognized by individual MHCI-restricted T-cell receptors. Immunology and Cell Biology 94 (6) , pp. 573-582. 10.1038/icb.2016.12

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Evidence indicates that autoimmunity can be triggered by virus-specific CD8+ T cells that crossreact with self-derived peptide epitopes presented on the cell surface by major histocompatibility complex class I (MHCI) molecules. Identification of the associated viral pathogens is challenging because individual T-cell receptors can potentially recognize up to a million different peptides. Here, we generate peptide length-matched combinatorial peptide library (CPL) scan data for a panel of virus-specific CD8+ T-cell clones spanning different restriction elements and a range of epitope lengths. CPL scan data drove a protein database search limited to viruses that infect humans. Peptide sequences were ranked in order of likelihood of recognition. For all anti-viral CD8+ T-cell clones examined in this study, the index peptide was either the top-ranked sequence or ranked as one of the most likely sequences to be recognized. Thus, we demonstrate that anti-viral CD8+ T-cell clones are highly focused on their index peptide sequence and that ‘CPL-driven database searching’ can be used to identify the inciting virus-derived epitope for a given CD8+ T-cell clone. Moreover, to augment access to CPL-driven database searching, we have created a publicly accessible webtool. Application of these methodologies in the clinical setting may clarify the role of viral pathogens in the etiology of autoimmune diseases.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Nature Publishing Group
ISSN: 0818-9641
Date of First Compliant Deposit: 15 February 2017
Date of Acceptance: 18 January 2016
Last Modified: 24 Mar 2020 15:41

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