A non-canonical role of Myc in programming basal cells as sentinels of upper airway immunity during influenza infection

Abstract

The upper respiratory epithelium is a specialized barrier that integrates immune surveillance with the biomechanical requirements of the laryngotracheal axis. Despite the clinical prevalence of persistent airway dysfunction following viral infection, the region-specific mechanisms governing laryngotracheal injury and repair remain poorly defined. Using integrated mouse models, imaging, and single-cell transcriptomics, we dissected IAV-induced injury in the upper respiratory tract. We found that infection displays regionally restricted tropism to subglottic and tracheal pseudostratified epithelia, targeting ciliated, secretory, neuroendocrine, and basal cells. Rapid viral clearance was accompanied by acute neutrophil infiltration and the emergence of a previously unrecognized intraepithelial CD8+ natural killer T (NKT)-like effector population. Functional studies revealed that injury-induced Myc expression in KRT5+ basal progenitors is required for mucosal restoration; while basal-specific Myc deletion preserved viral clearance, it attenuated proliferation and impaired the recruitment of CD8+ NKT cells. Together, these findings delineate a coordinated epithelial-immune circuit governing post-viral mucosal restoration, positioning basal cells as specialized epithelial sentinels that orchestrate acute repair and recruit cytotoxic effectors via a MYC-dependent CXCL10-CXCR3 axis.