title: Identification of human viral protein-derived ligands recognized by individual MHCI-restricted T-cell receptors.
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.
authors: Warwick Systems Biology Centre, University of Warwick, Coventry, UK.|Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.
authors: Barbara
authors: B
authors: Szomolay
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors: Jie
authors: J
authors: Liu
authors: Warwick Systems Biology Centre, University of Warwick, Coventry, UK.
authors: Paul E
authors: PE
authors: Brown
authors: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors: John J
authors: JJ
authors: Miles
authors: Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.
authors: Mathew
authors: M
authors: Clement
authors: Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.
authors: Sian
authors: S
authors: Llewellyn-Lacey
authors: Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.
authors: Garry
authors: G
authors: Dolton
authors: Wright Fleming Wing, St Mary's Campus, Imperial College, London, UK.
authors: Julia
authors: J
authors: Ekeruche-Makinde
authors: Faculty of Health Sciences, University of Bristol, Biomedical Sciences Building, Bristol, UK.
authors: Anya
authors: A
authors: Lissina
authors: Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.
authors: Andrea J
authors: AJ
authors: Schauenburg
authors: Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.
authors: Andrew K
authors: AK
authors: Sewell
authors: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors: Scott R
authors: SR
authors: Burrows
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors: Mario
authors: M
authors: Roederer
authors: Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.|Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors: David A
authors: DA
authors: Price
authors: Faculty of Health Sciences, University of Bristol, Biomedical Sciences Building, Bristol, UK.
authors: Linda
authors: L
authors: Wooldridge
authors: Warwick Systems Biology Centre, University of Warwick, Coventry, UK.
authors: Hugo A
authors: HA
authors: van den Berg
mesh_terms: D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D030562:Databases, Protein; D015497:HIV-1 / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015203:Reproducibility of Results; D013045:Species Specificity; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D015395:Histocompatibility Antigens Class I; D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins