Natural Killer Cell TGF-β Signaling Regulates Postnatal Lung Development

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a disease of neonatal lung development that is linked to impaired pulmonary vascularization, dysregulated TGF-β (transforming growth factor-β) signaling, and the accumulation of senescent cells. Despite the established role of TGF-β signaling in promoting vascular remodeling and suppressing the senolytic activity of natural killer (NK) cells, the contribution of NK cell TGF-β signaling to postnatal lung patterning and the pathogenesis of BPD remains unclear. METHODS: Mice bearing an NK cell-selective deletion of the type-II TGF-β receptor ( Tgfbr2 NK− /− ) were analyzed for vascular and alveolar structure, lung NK cell infiltration, senescence markers, and lung function testing across neonatal and adult time points. Lung tissue from both neonatal mice and human infants with BPD was assessed by single-cell RNA sequencing. The effects of enhanced NK cell activity in a hyperoxia-induced model of BPD were examined in Tgfbr2 NK−/− neonates, as well as pharmacologically, using the TGF-β ligand trap/IL-15 superagonist, HCW9218. RESULTS: Neonatal Tgfbr2 NK−/− mice exhibited a baseline reduction in distal arteriolar density, impaired alveolarization, and sex-specific deficits in long-term lung function. Single-cell RNA sequencing identified excessive clearance of senescent endothelial cells by TGF-β-insensitive NK cells in the lungs of Tgfbr2 NK−/− neonates. This enhanced NK cell activity promoted a BPD-like phenotype in naïve Tgfbr2 NK−/− mice but protected these animals from impaired lung development under hyperoxia. Sequencing of lung tissue from human infants with BPD confirmed excessive TGF-β signaling and cytotoxic impairment in NK cells. Treatment with HCW9218 prevented senescent cell accumulation and rescued lung development in the hyperoxia mouse model. CONCLUSIONS: TGF-β is a tunable regulator of NK cell senolytic activity that is essential for normal postnatal lung development. Excessive NK cell TGF-β signaling contributes to impaired lung development with neonatal hyperoxia and may serve as a viable therapeutic target in human BPD.