Contemporary Analysis of MHC-Related Immunodominance Hierarchies in the CD8+ T Cell Response to Influenza A Viruses

Abstract

Early studies of influenza virus-specific CD8+ T cell-mediated immunity indicated that the level of CTL activity associated with H2Db is greatly diminished in mice that also express H2Kk. Such MHC-related immunodominance hierarchies are of some interest, as they could lead to variable outcomes for peptide-based vaccination protocols in human populations. The influence of H2Kk on the H2Db-restricted response profile has thus been looked at again using a contemporary, quantitative, IFN-γ-based flow cytometric assay. The depressive effect of H2Kk was very apparent for the influenza DbPA224 epitope and was also reproduced when CTL activity was measured for H2Db-expressing targets pulsed with the immunodominant NP366 peptide. The secondary CD8+IFN-γ+ DbNP366-specific response was much greater in parental H2b than in H2k×bF1 mice, but the sizes of the CD8+ sets specific for KkNP50 and DbNP366 were essentially equivalent in the F1 animals. Thus, although the immunodominance profile associated with DbNP366 is lost when H2Kk is also present, the response is still substantial. A further, MHC-related effect was also identified for the KkNS1152 epitope, which was consistently associated with a greater CD8+IFN-γ+ response in H2KkDb recombinant than in (H2KkDk × H2KbDb)F1 mice. The diminished DbPA224 response in H2k×bF1 mice was characterized by loss of a prominent Vβ7 TCR responder phenotype, supporting the idea that TCR deletion during ontogeny shapes the available repertoire. The overall conclusion is that these MHC-related immunodominance hierarchies are more subtle than the early CTL assays suggested and, although inherently unpredictable, are unlikely to cause a problem for peptide-based vaccine strategies.