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.