Selective deletion of the natural killer cell type-II TGF-β receptor impairs murine lung development and function — ASN Events
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Selective deletion of the natural killer cell type-II TGF-β receptor impairs murine lung development and function (#164)

Declan J Gainer 1 , Kassandra M Coyle 1 , Matthew T Rätsep 2 , Douglas Quilty 2 , Marty M VandenBroek 1 , Kimberly Laverty 2 , Yupu Deng 3 , Duncan J Stewart 3 , Eric Vivier 4 5 , Nicolle J Domnik 2 , Niraj Shrestha 6 , Hing C Wong 6 , Mark L Ormiston 1 2
  1. Department of Medicine, Queen's University, Kingston, Ontario, Canada
  2. Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
  3. Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  4. Centre d'Immunologie de Marseille-Luminy, Marseille, France
  5. Aix-Marseille University, Marseille, France
  6. HCW Biologics Inc., Miramar, Florida, United States

Rationale: Bronchopulmonary dysplasia (BPD) is a leading cause of morbidity and mortality among preterm infants. The disease is marked by impaired airway and pulmonary vascular development, and is associated with the accumulation of senescent cells and dysregulated transforming growth factor-β (TGF-β) signaling. Though past studies have linked the suppression of NK cells by TGF-β to vascular remodeling in both pregnancy and cancer, the contributions of NK cell TGF-β signaling to pulmonary vascular development and the pathogenesis of BPD have yet to be explored.

Methods and Results: Immunofluorescent staining and lung MicroCT imaging identified a reduced pulmonary arteriolar density in adult mice bearing a natural killer cell-selective deletion of the type-II TGF-β receptor (Tgfbr2NK-/-). Assessment of neonatal pulmonary vascular and airway patterning revealed a BPD-like phenotype in Tgfbr2NK-/- mice by postnatal day 5 (P5), marked by impaired alveolarization and preceded by a reduced pulmonary arteriolar density at P3. Despite catch-up alveolarization, decreased pulmonary compliance persisted in adult male Tgfbr2NK-/- mice, accompanied by an increase in mean alveolar duct area. Single cell RNA sequencing of P3 lungs and senescence-associated β-galactosidase staining were used to identify an increased clearance of senescent cells from the lungs of Tgfbr2NK-/- neonates. In a model of hyperoxia-induced BPD characterized by dysregulated TGF-β signaling, treatment with HCW9218, an NK cell-activating senolytic consisting of a bifunctional TGF-β ligand trap fused to an IL-15/IL-15RɑSU (10 mg/kg, S.Q.), reduced senescent cell accumulation, partially protected against alveolar simplification, and restored pulmonary vascular density, relative to vehicle-treated controls.

Conclusions: We have demonstrated that both heightened and suppressed NK cell TGF-β signaling can influence senescent cell abundance and drive defective postnatal lung patterning. In doing so, we present the modulation of NK cell senolytic activity as a viable treatment strategy for BPD.