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, and Burrows, Scott 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, 194 (10). pp. 4668-4675.

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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.

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