Superdominance among immunodominant H-2Kb-restricted epitopes and reversal by dendritic cell-mediated antigen delivery

Abstract

To examine possible interference patterns between immunodominant CTL Ags, we analyzed the response to mixtures of five well-characterized H-2Kb-restricted epitopes, each of which had earlier been described as immunodominant within its antigenic system. Clear patterns of dominance were observed between peptides in the mixture, with the CTL response focusing on the Sendai virus nucleoprotein 324-332 and vesicular stomatitis virus nucleoprotein 52-59 epitopes. The dominance of these epitopes correlated with high CTL availability. Subdominance of the OVA(257-264) and the MCF1233 murine leukemia virus envelope 574-581 peptides could not be explained by inferior ability to bind and stabilize MHC class I molecules. Interestingly, immunodominance was broken if the peptide mixture was pulsed on bone marrow-derived dendritic cells, a mode of immunization allowing efficient recognition of a broader set of specificities. Our results show that immunodominance is neither an absolute feature of a given epitope nor does it apply only in relation to other epitopes within the same protein, micro-organism, or cell. Novel "superdominant" hierarchies emerge in the response against multiple "dominant" epitopes. A T cell competition model to explain the data in terms of a balance influenced by CTL frequencies and available APC capacity is discussed.