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T Cell Cross-Reactivity between a Highly Immunogenic EBV Epitope and a Self-Peptide Naturally Presented by HLA-B*18:01+ Cells.
J Immunol 2015; 194(10):4668-75JI

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+Show Affiliations

QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia; School of Medicine, University of Queensland, Brisbane, Queensland 4072, Australia;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.Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia;QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia;QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia;QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia;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.Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia;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.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25855358

Citation

Rist, Melissa J., et al. "T Cell Cross-Reactivity Between a Highly Immunogenic EBV Epitope and a Self-Peptide Naturally Presented By HLA-B*18:01+ Cells." Journal of Immunology (Baltimore, Md. : 1950), vol. 194, no. 10, 2015, pp. 4668-75.
Rist MJ, Hibbert KM, Croft NP, et al. T Cell Cross-Reactivity between a Highly Immunogenic EBV Epitope and a Self-Peptide Naturally Presented by HLA-B*18:01+ Cells. J Immunol. 2015;194(10):4668-75.
Rist, M. J., Hibbert, K. M., Croft, N. P., Smith, C., Neller, M. A., Burrows, J. M., ... Burrows, S. R. (2015). T Cell Cross-Reactivity between a Highly Immunogenic EBV Epitope and a Self-Peptide Naturally Presented by HLA-B*18:01+ Cells. Journal of Immunology (Baltimore, Md. : 1950), 194(10), pp. 4668-75. doi:10.4049/jimmunol.1500233.
Rist MJ, et al. T Cell Cross-Reactivity Between a Highly Immunogenic EBV Epitope and a Self-Peptide Naturally Presented By HLA-B*18:01+ Cells. J Immunol. 2015 May 15;194(10):4668-75. PubMed PMID: 25855358.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - T Cell Cross-Reactivity between a Highly Immunogenic EBV Epitope and a Self-Peptide Naturally Presented by HLA-B*18:01+ Cells. AU - Rist,Melissa J, AU - Hibbert,Kelly M, AU - Croft,Nathan P, AU - Smith,Corey, AU - Neller,Michelle A, AU - Burrows,Jacqueline M, AU - Miles,John J, AU - Purcell,Anthony W, AU - Rossjohn,Jamie, AU - Gras,Stephanie, AU - Burrows,Scott R, Y1 - 2015/04/08/ PY - 2015/02/02/received PY - 2015/03/12/accepted PY - 2015/4/10/entrez PY - 2015/4/10/pubmed PY - 2015/7/22/medline SP - 4668 EP - 75 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J. Immunol. VL - 194 IS - 10 N2 - 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. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/25855358/T_Cell_Cross_Reactivity_between_a_Highly_Immunogenic_EBV_Epitope_and_a_Self_Peptide_Naturally_Presented_by_HLA_B_18:01+_Cells_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=25855358 DB - PRIME DP - Unbound Medicine ER -