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Contemporary Analysis of MHC-Related Immunodominance Hierarchies in the CD8⁺ T Cell Response to Influenza A Viruses¹

Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105

Early studies of influenza virus-specific CD8⁺ T cell-mediated immunity indicated that the level of CTL activity associated with H2D^b is greatly diminished in mice that also express H2K^k. 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 H2K^k on the H2D^b-restricted response profile has thus been looked at again using a contemporary, quantitative, IFN--based flow cytometric assay. The depressive effect of H2K^k was very apparent for the influenza D^bPA₂₂₄ epitope and was also reproduced when CTL activity was measured for H2D^b-expressing targets pulsed with the immunodominant NP₃₆₆ peptide. The secondary CD8⁺IFN-⁺ D^bNP₃₆₆-specific response was much greater in parental H2^b than in H2^kxbF₁ mice, but the sizes of the CD8⁺ sets specific for K^kNP₅₀ and D^bNP₃₆₆ were essentially equivalent in the F₁ animals. Thus, although the immunodominance profile associated with D^bNP₃₆₆ is lost when H2K^k is also present, the response is still substantial. A further, MHC-related effect was also identified for the K^kNS1₁₅₂ epitope, which was consistently associated with a greater CD8⁺IFN-⁺ response in H2K^kD^b recombinant than in (H2K^kD^k x H2K^bD^b)F₁ mice. The diminished D^bPA₂₂₄ response in H2^kxbF₁ mice was characterized by loss of a prominent Vß7 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.

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