T Cell Cross-Reactivity between a Highly Immunogenic EBV Epitope and a Self-Peptide Naturally Presented by HLA-B18:01+ Cells

• Published in: The Journal of immunology (1950) 2015-05, Vol.194 (10), p.4668-4675
• Main Authors: Rist, Melissa J, Hibbert, Kelly M, Croft, Nathan P, Smith, Corey, Neller, Michelle A, Burrows, Jacqueline M, Miles, John J, Purcell, Anthony W, Rossjohn, Jamie, Gras, Stephanie, Burrows, Scott R
• Format: Article
• Language: English
• Subjects: Antigen Presentation - immunology; Antigens, Viral - immunology; Autoantigens - immunology; Autoimmunity - immunology; CD8-Positive T-Lymphocytes - immunology; Chromatography, Liquid; Cross Reactions - immunology; Epitopes, T-Lymphocyte - immunology; Epstein-Barr virus; Epstein-Barr Virus Infections - immunology; Herpesvirus 4, Human - immunology; HLA-B Antigens - immunology; Humans; Molecular Mimicry - immunology; Tandem Mass Spectrometry
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1500233

T cell cross-reactivity underpins the molecular mimicry hypothesis in which microbial peptides sharing structural features with host peptides stimulate T cells that cross-react with self-peptides, thereby initiating and/or perpetuating autoimmune disease. EBV represents a potentially important factor in the pathogenesis of several T cell-mediated autoimmune disorders, with molecular mimicry a likely mechanism. In this study, we describe a human self-peptide (DELEIKAY) that is a homolog of a highly immunogenic EBV T cell epitope (SELEIKRY) presented by HLA-B*18:01. This self-peptide was shown to bind stably to HLA-B*18:01, and peptide elution/mass spectrometric studies showed it is naturally presented by this HLA molecule on the surface of human cells. A significant proportion of CD8(+) T cells raised from some healthy individuals against this EBV epitope cross-reacted with the self-peptide. A diverse array of TCRs was expressed by the cross-reactive T cells, with variable functional avidity for the self-peptide, including some T cells that appeared to avoid autoreactivity by a narrow margin, with only 10-fold more of the self-peptide required for equivalent activation as compared with the EBV peptide. Structural studies revealed that the self-peptide-HLA-B*18:01 complex is a structural mimic of the EBV peptide-HLA-B*18:01 complex, and that the strong antiviral T cell response is primarily dependent on the alanine/arginine mismatch at position 7. To our knowledge, this is the first report confirming the natural presentation of a self-peptide cross-recognized in the context of self-HLA by EBV-reactive CD8(+) T cells. These results illustrate how aberrant immune responses and immunopathological diseases could be generated by EBV infection.