Consequences of suboptimal priming are apparent for low-avidity T-cell responses.

The emergence of the novel reassortant A(H1N1)-2009 influenza virus highlighted the threat to the global population posed by an influenza pandemic. Pre-existing CD8⁺ T-cell immunity targeting conserved epitopes provides immune protection against newly emerging strains of influenza virus, when minimal antibody immunity exists. However, the occurrence of mutations within T-cell antigenic peptides that enable the virus to evade T-cell recognition constitutes a substantial issue for virus control and vaccine design. Recent evidence suggests that it might be feasible to elicit CD8⁺ T-cell memory pools to common virus mutants by pre-emptive vaccination. However, there is a need for a greater understanding of CD8⁺ T-cell immunity towards commonly emerging mutants. The present analysis focuses on novel and immunodominant, although of low pMHC-I avidity, CD8⁺ T-cell responses directed at the mutant influenza D^bNP₃₆₆ epitope, D^bNPM6A, following different routes of infection. We used a C57BL/6J model of influenza to dissect the effectiveness of the natural intranasal (i.n.) versus intraperitoneal (i.p.) priming for generating functional CD8⁺ T cells towards the D^bNPM6A epitope. In contrast to comparable CD8⁺ T-cell responses directed at the wild-type epitopes, D^bNP₃₆₆ and D^bPA₂₂₄, we found that the priming route greatly affected the numbers, cytokine profiles and TCR repertoire of the responding CD8⁺ T cells directed at the D^bNPM6A viral mutant. As the magnitude, polyfunctionality, and T-cell repertoire diversity are potential determinants of the protective efficacy of CD8⁺ T-cell responses, our data have implications for the development of vaccines to combat virus mutants. [ABSTRACT FROM AUTHOR]