title: T Cell Cross-Reactivity between a Highly Immunogenic EBV Epitope and a Self-Peptide Naturally Presented by HLA-B*18:01+ Cells.
abstract: 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.
authors: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia; School of Medicine, University of Queensland, Brisbane, Queensland 4072, Australia;
authors: Melissa J
authors: MJ
authors: Rist
authors: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia; and.
authors: Kelly M
authors: KM
authors: Hibbert
authors: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia;
authors: Nathan P
authors: NP
authors: Croft
authors: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia;
authors: Corey
authors: C
authors: Smith
authors: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia;
authors: Michelle A
authors: MA
authors: Neller
authors: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia;
authors: Jacqueline M
authors: JM
authors: Burrows
authors: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia; School of Medicine, University of Queensland, Brisbane, Queensland 4072, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors: John J
authors: JJ
authors: Miles
authors: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia;
authors: Anthony W
authors: AW
authors: Purcell
authors: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia; and Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom Scott.Burrows@qimrberghofer.edu.au Stephanie.Gras@monash.edu Jamie.Rossjohn@monash.edu.
authors: Jamie
authors: J
authors: Rossjohn
authors: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia; and Scott.Burrows@qimrberghofer.edu.au Stephanie.Gras@monash.edu Jamie.Rossjohn@monash.edu.
authors: Stephanie
authors: S
authors: Gras
authors: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia; School of Medicine, University of Queensland, Brisbane, Queensland 4072, Australia; Scott.Burrows@qimrberghofer.edu.au Stephanie.Gras@monash.edu Jamie.Rossjohn@monash.edu.
authors: Scott R
authors: SR
authors: Burrows
mesh_terms: D017951:Antigen Presentation / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002853:Chromatography, Liquid; D003429:Cross Reactions / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D020031:Epstein-Barr Virus Infections / Q000276:immunology; D015235:HLA-B Antigens / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D018716:Molecular Mimicry / Q000276:immunology; D053719:Tandem Mass Spectrometry
chemical_list: D000956:Antigens, Viral; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens