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 J., Sewell, Andrew K., Burrows, Scott R., Roederer, Mario, Price, David A., 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.

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Abstract

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 ID: 44961
Item Type: Article (Research - C1)
ISSN: 1440-1711
Additional Information:

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license,users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Funders: Biotechnology and Biological Sciences Research Council (BBSRC), Wellcome Trust (WT)
Projects and Grants: BBSRC Grant BB/H001085/1, WT079848MA
Date Deposited: 03 Aug 2016 02:46
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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