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bioRxiv · 10.1101/2025.08.29.673190

Natural killer cell TGF- signaling regulates senolytic activity and vascular patterning in the postnatal lung

Gainer, D. J.·Coyle, K. M.·Rätsep, M. T.·Quilty, D.·Tran, B.·Skebo, S. I.·VandenBroek, M. M.·Laverty, K. J.·Deng, Y.·Shirazi, S. P.·Brady, H. J. M.·Sucre, J. M. S.·Vivier, E.·Shrestha, N.·Wong, H. C.·Stewart, D. J.·Domnik, N. J.·Ormiston, M. L.
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Abstract

BackgroundBronchopulmonary dysplasia (BPD) is a disease of neonatal lung development that is linked to impaired pulmonary vascularization, dysregulated transforming growth factor-{beta} (TGF-{beta}) signaling and the accumulation of senescent cells. Despite the established role for TGF-{beta} signaling in promoting vascular remodeling and suppressing the senolytic activity of natural killer (NK) cells, the contribution of NK cell TGF-{beta} signaling to postnatal lung patterning and the pathogenesis of BPD remains unclear. MethodsMice bearing an NK cell-selective deletion of the type-II TGF-{beta} receptor (Tgfbr2NK-/-) were analyzed for vascular and alveolar structure, lung NK cell infiltration, senescence markers and lung function testing across neonatal and adult timepoints. Single-cell RNA sequencing of lung tissue from both neonatal mice and human infants with BPD was performed. The effect of enhanced NK cell activity in a hyperoxia-induced model of BPD was assessed in Tgfbr2NK-/-neonates, as well as pharmacologically, using the TGF-{beta} ligand trap/IL-15 superagonist, HCW9218. ResultsNeonatal Tgfbr2NK-/- 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 the excessive clearance of senescent endothelial cells by TGF-{beta} insensitive NK cells in the lungs of Tgfbr2NK-/- neonates, which served as a contributor of the BPD-like phenotype observed in naive animals. Tgfbr2NK-/- mice were protected from impaired lung development in the hyperoxia model. Sequencing from lung tissue from infants with BPD confirmed excessive TGF-{beta} signaling and cytotoxic impairment in NK cells. Treatment with HCW9218 prevented senescent cell accumulation and rescued lung development in the hyperoxia mouse model. ConclusionsThese findings identify TGF-{beta} as a tunable regulator of NK cell senolytic activity that is essential to normal postnatal lung development. Excessive NK cell TGF-{beta} signaling contributes to impaired lung development following exposure to neonatal hyperoxia and may serve as a viable therapeutic target for human BPD.

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Gainer, D. J., Coyle, K. M., Rätsep, M. T., Quilty, D., Tran, B., Skebo, S. I., VandenBroek, M. M., Laverty, K. J., Deng, Y., Shirazi, S. P., Brady, H. J. M., Sucre, J. M. S., Vivier, E., Shrestha, N., Wong, H. C., Stewart, D. J., Domnik, N. J., Ormiston, M. L.. 2025-09-04. Natural killer cell TGF- signaling regulates senolytic activity and vascular patterning in the postnatal lung. https://doi.org/10.1101/2025.08.29.673190

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