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

Barbara Szomolay, Jie Liu, Paul Brown, Mathew Clement, Sian Llewellyn-Lacey, Garry Dolton, Julia Ekeruche-Makinde, Anya Lissina, Andrea J A Schauenburg, Andrew K Sewell, Scott R Burrows, Mario Roederer, David A Price, Linda Wooldridge, Hugo A van den Berg

Research output: Contribution to journalArticle (Academic Journal)peer-review

11 Citations (Scopus)
216 Downloads (Pure)

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 (TCRs) 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, restricted to viruses that infect humans. Peptide sequences were ranked in order of likelihood recognition. For all anti-viral CD8+ T-cell clones examined, 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.
Original languageEnglish
Pages (from-to)573–582
Number of pages10
JournalImmunology and Cell Biology
Volume94
Issue number6
Early online date29 Mar 2016
DOIs
Publication statusPublished - Jul 2016

Keywords

  • T-cell activation
  • T-cell crossreactivity
  • autoimmunity
  • cancer
  • alloreactivity
  • leukaemia
  • T-cell expansions
  • MHCI
  • T-cell receptor

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