Human CD8+ T cell response in the lower airways during acute seasonal influenza infection

Lung tissue-resident CD8+ T cells facilitate viral clearance and protective immunity to influenza viruses in animal models. Their role during acute human infection is not clear. We use bronchoalveolar lavage samples collected from human subjects naturally infected with influenza B virus during the 2019-2020 influenza season to show that influenza-specific CD8+ T cells robustly expand in the lower airways during acute infection and target only a few epitopes from phylogenetically conserved internal influenza virus proteins. The expansion hierarchy of lower airway influenza-specific CD8+ T cells is not reflected in matched blood samples. Transcriptional analysis reveals a tissue-resident profile and less expression of cytotoxic effector molecules in lower airway influenza-specific CD8+ T cells. Collectively, we show that high-frequency, influenza-specific, mucosal tissue-resident CD8+ T cells recognizing a handful of conserved epitopes and exhibiting a unique functional phenotype expand in the lower airways during viral clearance, suggesting a role in controlling human infection.