Potential killers exposed: tracking endogenous influenza-specific CD8⁺ T cells

Current influenza A virus (IAV) vaccines stimulate antibody responses that are directed against variable regions of the virus, and are therefore ineffective against divergent strains. As CD8⁺ T cells target the highly conserved, internal IAV proteins, they have the potential to increase heterosubtypic immunity. Early T-cell priming events influence lasting memory, which is required for long-term protection. However, the early responding, IAV-specific cells are difficult to monitor because of their low frequencies. Here, we tracked the dissemination of endogenous IAV-specific CD8⁺ T cells during the initial phases of the immune response following IAV infection. We exposed a significant population of recently activated, CD25⁺ CD43⁺ IAV-specific T cells that were not detected by tetramer staining. By tracking this population, we found that initial T-cell priming occurred in the mediastinal lymph nodes, which gave rise to the most expansive IAV-specific CD8⁺ T-cell population. Subsequently, IAV-specific CD8⁺ T cells dispersed to the bronchoalveolar lavage and blood, followed by spleen and liver, and finally to the lung. These data provide important insight into the priming and tissue dispersion of an endogenous CD8⁺ T-cell response. Importantly, the CD25⁺ CD43⁺ phenotype identifies an inclusive population of early responding CD8⁺ T cells, which may provide insight into TCR repertoire selection and expansion. A better understanding of this response is critical for designing improved vaccines that target CD8⁺ T cells.