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.