Virus-specific effector T cells impair airway secretory cell-mediated alveolar regeneration

Severe respiratory viral infection leads to extensive damage to the alveolar epithelium and also induce a robust immune response. How immune response impacts alveolar regeneration, especially how immune microenvironment interacts with lung stem/progenitor cells is poorly understood. Here, we find that dysplastic Krt5+ basal-like cells, which emerge after severe viral infection, preferably recruit and maintain the tissue residence of both CD4+ effector T cells and CD8+ T cells in a CXCR3- and Integrin a4/ß2-dependent manner after viral clearance. Persistent CD4+ and CD8+ T cells impair alveolar regeneration mediated by airway secretory cells, thus inhibiting lung functional repair. Mechanically, CD4+ and CD8+ T cells function by secreting IFN? rather than direct interactions with epithelial cells. Importantly, anti-IFN? treatment promotes alveolar regeneration and functional recovery in vivo. Overall, our study reveals the pathogenetic role of Krt5+ pods in lung regeneration, providing new insights into how dysplastic repair impairs functional regeneration of the alveolar epithelium via interactions with immune cells. Overall design: Airway epithelial cells (CD45- EPCAM+ CD31- Integrin ß4+) from the lungs of influenza-infected mice at 11 days post-infection (dpi) were isolated using FACS. These cells were then cultured in1:1 mixed SAGM and LPM medium without CHIR medium for 10 days before being digested into single cells for scRNA-seq analysis.