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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.","bibjson":{"author":[{"initials":"MJ","lastname":"Rist","name":"Rist MJ"},{"initials":"KM","lastname":"Hibbert","name":"Hibbert KM"},{"initials":"NP","lastname":"Croft","name":"Croft NP"},{"initials":"C","lastname":"Smith","name":"Smith C"},{"initials":"MA","lastname":"Neller","name":"Neller MA"},{"initials":"JM","lastname":"Burrows","name":"Burrows JM"},{"initials":"JJ","lastname":"Miles","name":"Miles JJ"},{"initials":"AW","lastname":"Purcell","name":"Purcell AW"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"S","lastname":"Gras","name":"Gras S"},{"initials":"SR","lastname":"Burrows","name":"Burrows SR"}],"identifier":[{"id":"10.4049/jimmunol.1500233","type":"doi"},{"id":"25855358","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"J. 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