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Pre-existing CD8(+) T-cell immunity directed towards conserved internal viral regions can greatly ameliorate the disease. However, mutational escape within the T cell epitopes is a substantial issue for virus control and vaccine design. Although mutations can result in a loss of T cell recognition, some variants generate cross-reactive T cell responses. In this study, we used reverse genetics to modify the influenza NP(336-374) peptide at a partially-solvent exposed residue (N->A, NPN3A mutation) to assess the availability, effectiveness and mechanism underlying influenza-specific cross-reactive T cell responses. The engineered virus induced a diminished CD8(+) T cell response and selected a narrowed T cell receptor (TCR) repertoire within two V beta regions (V beta 8.3 and V beta 9). This can be partially explained by the H-2D(b)NPN3A structure that showed a loss of several contacts between the NPN3A peptide and H-2D(b), including a contact with His155, a position known to play an important role in mediating TCR-pMHC-I interactions. Despite these differences, common cross-reactive TCRs were detected in both the na\u00efve and immune NPN3A-specific TCR repertoires. However, while the NPN3A epitope primes memory T-cells that give an equivalent recall response to the mutant or wild-type (wt) virus, both are markedly lower than wt->wt challenge. Such decreased CD8(+) responses elicited after heterologous challenge resulted in delayed viral clearance from the infected lung. Furthermore, mice first exposed to the wt virus give a poor, low avidity response following secondary infection with the mutant. Thus, the protective efficacy of cross-reactive CD8(+) T cells recognising mutant viral epitopes depend on peptide-MHC-I structural interactions and functional avidity. Our study does not support vaccine strategies that include immunization against commonly selected cross-reactive variants with mutations at partially-solvent exposed residues that have characteristics comparable to NPN3A.","bibjson":{"author":[{"initials":"SA","lastname":"Valkenburg","name":"Valkenburg SA"},{"initials":"S","lastname":"Gras","name":"Gras S"},{"initials":"C","lastname":"Guillonneau","name":"Guillonneau C"},{"initials":"NL","lastname":"La Gruta","name":"La Gruta NL"},{"initials":"PG","lastname":"Thomas","name":"Thomas PG"},{"initials":"AW","lastname":"Purcell","name":"Purcell AW"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"PC","lastname":"Doherty","name":"Doherty PC"},{"initials":"SJ","lastname":"Turner","name":"Turner SJ"},{"initials":"K","lastname":"Kedzierska","name":"Kedzierska K"}],"identifier":[{"id":"10.1371/journal.ppat.1001039","type":"doi"},{"id":"20711359","type":"pubmed"}],"issue":["8"],"journal":{"iso_abbreviation":"PLoS Pathog.","name":""},"pages":["e1001039"],"title":"Protective efficacy of cross-reactive CD8+ T cells recognising mutant viral epitopes depends on peptide-MHC-I structural interactions and T cell activation threshold.","type":"article","url":"https://dx.plos.org/10.1371/journal.ppat.1001039","volume":["6"],"year":[2010]},"in_pmc":"Y","in_pmce":"Y","open_access":"Y"},"resolution":"2.60","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/3ftg"},"rcsb":{"url":"https://www.rcsb.org/structure/3ftg"}},"species":{"common_name":"Mouse","match_type":"histo:assign_species","scientific_name":"Mus musculus","slug":"mus_musculus"},"tcr":null,"title":"H2-Db binding \"ASAENMETM\" at 2.60Å resolution","unique_chain_count":3}}