Natural killer cell TGF-β signaling regulates senolytic activity and vascular patterning in the postnatal lung
Bibliographic record
Abstract
Abstract Background Bronchopulmonary dysplasia (BPD) is a disease of neonatal lung development that is linked to impaired pulmonary vascularization, dysregulated transforming growth factor-β (TGF-β) signaling and the accumulation of senescent cells. Despite the established role for 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 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 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 the excessive clearance of senescent endothelial cells by TGF-β insensitive NK cells in the lungs of Tgfbr2 NK-/- neonates, which served as a contributor of the BPD-like phenotype observed in naïve animals. Tgfbr2 NK-/- mice were protected from impaired lung development in the hyperoxia model. Sequencing from lung tissue from 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 These findings identify TGF-β as a tunable regulator of NK cell senolytic activity that is essential to normal postnatal lung development. Excessive NK cell TGF-β 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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".