Human lung CD8+ tissue-resident memory T cell-derived interferon-γ orchestrates subset-specific antiviral programming in airway epithelial cells

Lung resident CD8⁺ T cells are situated at the site of initial viral entry and replication. Here, we examined the phenotypic profiles and effector functions of human lung CD8⁺ T cells specific for four prevalent human viruses-influenza, respiratory syncytial virus (RSV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). Virus-specific lung CD8⁺ T cells exhibited distinct tissue-resident memory (Trm) phenotypes based on viral tropism yet shared core transcriptional and effector programs. Cognate antigen stimulation of lung Trm cells triggered interferon-γ (IFNγ)-mediated activation programs in lung innate immune and airway epithelial cells. Basal epithelial cells were most responsive to IFNγ, with differential expression of IFN-stimulated gene pathways in basal and secretory epithelial cell subsets following CD8⁺ Trm cell activation. In air-liquid interface cultures modeling influenza infection of the lung, rapid IFNγ signaling was necessary and sufficient to activate antiviral pathways in stratified epithelium and protect against infection. Thus, lung Trm cells coordinate early mucosal defense through rapid IFNγ-driven epithelial programming to restrict respiratory virus propagation in humans.