CTL Recognition of a Protective Immunodominant Influenza A Virus Nucleoprotein Epitope Utilizes a Highly Restricted Vβ but Diverse Vα Repertoire: Functional and Structural Implications

To investigate protective immunity conferred by CTL against viral pathogens, we have analyzed CD8+ T cell responses to the immunodominant nucleoprotein epitope (NP366–374) of influenza A virus in B6 mice during primary and secondary infections in vivo. Unlike the highly biased TCR Vβ repertoire, the associated Vα repertoire specific for the NP366–374/Db ligand is quite diverse. Nonetheless, certain public and conserved CDR3α clonotypes with distinct molecular signatures were identified. Pairing of public Vα and Vβ domains creates an αβ TCR heterodimer that binds efficiently to the NP366–374/Db ligand and stimulates T cell activation. In contrast, private TCRs, each comprising a distinct α chain paired with the same public β chain, interact very differently. Molecular dynamics simulation reveals that the conformation and mobility of the shared Vβ CDR loops are governed largely by the associated Vα domains. These results provide insight into molecular principles regarding public versus private TCRs linked to immune surveillance after infection with influenza A virus.