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

Immunol Cell Biol. 2016 Jul;94(6):573-82. doi: 10.1038/icb.2016.12. Epub 2016 Feb 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • CD8-Positive T-Lymphocytes / immunology
  • Databases, Protein
  • HIV-1 / immunology
  • Herpesvirus 4, Human / immunology
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Ligands
  • Peptide Library
  • Peptides / chemistry
  • Peptides / metabolism
  • Receptors, Antigen, T-Cell / metabolism*
  • Reproducibility of Results
  • Species Specificity
  • Viral Proteins / metabolism*

Substances

  • Histocompatibility Antigens Class I
  • Ligands
  • Peptide Library
  • Peptides
  • Receptors, Antigen, T-Cell
  • Viral Proteins