Differential Antigen Presentation Regulates the Changing Patterns of CD8(+) T Cell Immunodominance in Primary and Secondary Influenza Virus Infections

The specificity of CD8(+) T cell responses can vary dramatically between primary and secondary infections. For example, NP(366–374)/D(b)- and PA(224–233)/D(b)-specific CD8(+) T cells respond in approximately equal numbers to a primary influenza virus infection in C57BL/6 mice, whereas NP(366–374)/D(b)-specific CD8(+) T cells dominate the secondary response. To investigate the mechanisms underlying this changing pattern of immunodominance, we analyzed the role of antigen presentation in regulating the specificity of the T cell response. The data show that both dendritic and nondendritic cells are able to present the NP(366–374)/D(b) epitope, whereas only dendritic cells effectively present the PA(224–233)/D(b) epitope after influenza virus infection, both in vitro and in vivo. This difference in epitope expression favored the activation and expansion of NP(366–374)/D(b)-specific CD8(+) memory T cells during secondary infection. The data also show that the immune response to influenza virus infection may involve T cells specific for epitopes, such as PA(224–233)/D(b), that are poorly expressed at the site of infection. In this regard, vaccination with the PA(224–233) peptide actually had a detrimental effect on the clearance of a subsequent influenza virus infection. Thus, differential antigen presentation impacts both the specificity of the T cell response and the efficacy of peptide-based vaccination strategies.