Highly focused human CD8+ T-cell response in the lower airways during acute 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. Here we use bronchoalveolar lavage samples collected from human subjects naturally infected with influenza B virus to show that influenza-specific CD8+ T cells are expanded in the lower airways during acute infection and target only a few epitopes from phylogenetically conserved internal influenza virus proteins. The lower airway influenza-specific CD8+ T-cell immunodominance hierarchy is different from the hierarchy observed in matched blood samples. Transcriptional and protein-level analyses using HLA class I tetramers reveal a tissue-resident profile and less expression of cytotoxic effector molecules in lower airway influenza-specific CD8+ T cells. Collectively, our data show that high-frequency influenza-specific CD8+ T cells with a tissue-resident phenotype are found in the lower airways during viral clearance. These cells recognize a handful of conserved viral epitopes and exhibit a functional phenotype different from cells found in blood. These cells may play a role in controlling human influenza infection.