Protective efficacy of cross-reactive CD8+ T cells recognising mutant viral epitopes depends on peptide-MHC-I structural interactions and T cell activation threshold.

摘要: Emergence of a new influenza strain leads to rapid global spread the virus due minimal antibody immunity. Pre-existing CD8+ T-cell immunity directed towards conserved internal viral regions can greatly ameliorate disease. However, mutational escape within T cell epitopes is substantial issue for control and vaccine design. Although mutations result in loss recognition, some variants generate cross-reactive responses. In this study, we used reverse genetics modify NP336–374 peptide at partially-solvent exposed residue (N->A, NPN3A mutation) assess availability, effectiveness mechanism underlying influenza-specific The engineered induced diminished response selected narrowed receptor (TCR) repertoire two Vβ (Vβ8.3 Vβ9). This be partially explained by H-2DbNPN3A structure that showed several contacts between H-2Db, including contact with His155, position known play an important role mediating TCR-pMHC-I interactions. Despite these differences, common TCRs were detected both naive immune NPN3A-specific TCR repertoires. while epitope primes memory T-cells give equivalent recall mutant or wild-type (wt) virus, are markedly lower than wt->wt challenge. Such decreased responses elicited after heterologous challenge resulted delayed clearance from infected lung. Furthermore, mice first wt poor, low avidity following secondary infection mutant. Thus, protective efficacy cells recognising depend on peptide-MHC-I structural interactions functional avidity. Our study does not support strategies include immunization against commonly residues have characteristics comparable NPN3A.