Contemporary analysis of MHC-related immunodominance hierarchies in the CD8(+) T cell response to influenza A viruses

Early studies of influenza virus-specific CD8(+) T cell-mediated immunity i ndicated that the level of CTL activity associated with H2D(b) is greatly d iminished in mice that also express H2K(k). Such MHC-related immunodominanc e hierarchies are of some interest, as they could lead to variable outcomes for peptide-based vaccination protocols in human populations, The influenc e of H2Kk on the H2D(b)-restricted response profile has thus been looked at again using a contemporary, quantitative, IFN-gamma -based flow cytometric assay, The depressive effect of H2K(k) was very apparent for the influenza D(b)PA(224) epitope and was also reproduced when CTL activity was measured for H2D(b)-expressing targets pulsed with the immunodominant NP,,, peptide , The secondary CD8(+)IFN-gamma (+) (DNP366)-N-b-specific response was much greater in parental H2(b) than in H2(kxb)F(1) mice, but the sizes of the C D8+ sets specific for (KNP50)-N-k and (DNP366)-N-b, were essentially equiva lent in the F-1 animals. Thus, although the immunodominance profile associa ted with (DNP366)-N-b is lost when H2Kk is also present, the response is st ill substantial, A further, MHC-related effect was also identified for the K(k)NS1(152) epitope, which was consistently associated with a greater CD8( +)IFN-gamma (+) response in H2k(k)D(b) recombinant than in (H2K(k)D(k) x H2 K(b)D(b))F-1 mice. The diminished D(b)PA(224) response in H2(kxb)F(1) mice was characterized by loss of a prominent V beta7 TCR responder phenotype, s upporting the idea that TCR deletion during ontogeny shapes the available r epertoire, The overall conclusion is that these MHC-related immunodominance hierarchies are more subtle than the early CTL assays suggested and, altho ugh inherently unpredictable, are unlikely to cause a problem for peptide-b ased vaccine strategies.