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cell receptor (TCR) genetic diversity is outnumbered by the quantity of pathogenic epitopes to be recognized. To provide efficient protective anti-viral immunity, a single TCR ideally needs to cross-react with a multitude of pathogenic epitopes. However, the frequency, extent, and mechanisms of TCR cross-reactivity remain unclear, with conflicting results on anti-viral T cell cross-reactivity observed in humans. Namely, both the presence and lack of T cell cross-reactivity have been reported with HLA-A*02:01-restricted epitopes from the Epstein-Barr and influenza viruses (BMLF-1 and M1<sub>58</sub>, respectively) or with the hepatitis C and influenza viruses (NS3<sub>1073</sub> and NA<sub>231</sub>, respectively). Given the high sequence similarity of these paired viral epitopes (56 and 88%, respectively), the ubiquitous nature of the three viruses, and the high frequency of the HLA-A*02:01 allele, we selected these epitopes to establish the extent of T cell cross-reactivity. We combined ex vivo and in vitro functional assays, single-cell \u03b1\u03b2TCR repertoire sequencing, and structural analysis of these four epitopes in complex with HLA-A*02:01 to determine whether they could lead to heterologous T cell cross-reactivity. Our data show that sequence similarity does not translate to structural mimicry of the paired epitopes in complexes with HLA-A*02:01, resulting in induction of distinct \u03b1\u03b2TCR repertoires. The differences in epitope architecture might be an obstacle for TCR recognition, explaining the lack of T cell cross-reactivity observed. In conclusion, sequence similarity does not necessarily result in structural mimicry, and despite the need for cross-reactivity, antigen-specific TCR repertoires can remain highly specific.","bibjson":{"author":[{"initials":"EJ","lastname":"Grant","name":"Grant EJ"},{"initials":"TM","lastname":"Josephs","name":"Josephs TM"},{"initials":"SA","lastname":"Valkenburg","name":"Valkenburg SA"},{"initials":"L","lastname":"Wooldridge","name":"Wooldridge L"},{"initials":"M","lastname":"Hellard","name":"Hellard M"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"M","lastname":"Bharadwaj","name":"Bharadwaj M"},{"initials":"K","lastname":"Kedzierska","name":"Kedzierska K"},{"initials":"S","lastname":"Gras","name":"Gras S"}],"identifier":[{"id":"10.1074/jbc.M116.753988","type":"doi"},{"id":"27645996","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"J. Biol. 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