Dysplastic epithelial repair promotes the tissue residence of lymphocytes to inhibit alveolar regeneration post viral infection.

Abstract

Severe respiratory viral infections lead to extensive damage to the alveolar epithelium and also induce a robust immune response. How the immune microenvironment interacts with lung stem/progenitor cells and impacts alveolar regeneration is poorly understood. Here, we found that dysplastic KRT5⁺ basal-like cells, which emerge after severe viral infections, contribute to the recruitment and sequestration of CD4⁺ effector and CD8⁺ T cells in the lung after viral clearance in a CXCR3- and integrin α4β7-dependent manner. Persistent CD4⁺ effector and CD8⁺ T cells impair alveolar regeneration mediated via airway secretory cells by secreting IFNγ, thereby inhibiting lung functional repair. Importantly, anti-IFNγ treatment improves alveolar regeneration and lung function in vivo. Overall, our study reveals the pathogenetic role of dysplastic KRT5⁺ cells in alveolar regeneration, serving as a niche for tissue-resident lymphocytes that specifically inhibit alveolar regeneration. Additionally, our findings provide a potential therapeutic strategy to improve alveolar regeneration after viral pneumonia.