The memory phase of the CD4 T-cell response to influenza virus infection maintains its diverse antigen specificity

A major gap in our understanding of the immune response to pathogens and vaccines is how closely the antigen specificity in the memory phase mimics repertoire that is rapidly expanded upon priming. Understanding the diversity of the CD4 T-cell memory compartment after a primary response to pathogens is hampered by the technical challenges of epitope discovery and suitable models to study primary immune responses. Recently, we have used overlapping synthetic peptides to empirically map most of the specificities present in the primary response to live influenza infection. We found that the CD4 T-cell response can be exceptionally diverse, depending on the allele(s) of MHC class II molecules expressed. In the current study, using a mouse model of primary influenza infection and peptide-specific cytokine EliSpots, we have asked how this broad CD4 T-cell immunodominance hierarchy changes as the immune response contracts and memory is established. Our studies revealed that, for the most part, diversity is maintained, and most specificities, including those for relatively minor epitopes, are preserved in the memory CD4 T-cell compartment. A modest, but reproducible shift in specificity toward haemagglutinin-derived epitopes was observed, raising the possibility that protein or peptide persistence might play a role in the evolution of the memory phase of the CD4 T-cell response.