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Alveolar type 2 (AT2) cells are heterogeneous cells, with specialised AT2 subpopulations within this lineage exhibiting stem cell properties. However, the existence of quiescent, immature cells within the AT2 lineage that are activated during lung regeneration is unknown.   Sftpc CreERT2/+ ;tdTomato flox/flox   mice were used for the labelling of AT2 cells and labelled subpopulations were analysed by flow cytometry, quantitative PCR, assay for transposase-accessible chromatin using sequencing (ATAC-seq), gene arrays, pneumonectomy and culture of precision-cut lung slices. Single-cell RNA-sequencing (scRNA-seq) data from human lungs were analysed.  In mice, we detected two distinct AT2 subpopulations, with low tdTomato level (Tom Low ) and high tdTomato level (Tom High ). Tom Low  cells express lower levels of the AT2 differentiation markers  Fgfr2b  and  Etv5 , while Tom High , as  bona fide  mature AT2 cells, show higher levels of  Sftpc ,  Sftpb ,  Sftpa1 ,  Fgfr2b  and  Etv5  expression. ATAC-seq analysis indicates that Tom Low  and Tom High  cells constitute two distinct cell populations, with specific silencing of  Sftpc ,  Rosa26  and cell cycle gene loci in the Tom Low  population. Upon pneumonectomy, the number of Tom Low  but not Tom High  cells increases and Tom Low  cells show upregulated expression of  Fgfr2b ,  Etv5 ,  Sftpc ,  Ccnd1  and  Ccnd2  compared to Sham. Tom Low  cells overexpress programmed cell death 1 ligand 1 (PD-L1), an immune inhibitory membrane receptor ligand, which is used by flow cytometry to differentially isolate these two subpopulations. In the human lung, data mining of a recent scRNA-seq AT2 data set demonstrates the existence of a  PD-L1  Pos  population. Therefore, we have identified a novel population of AT2 quiescent, immature progenitor cells in mouse that expand upon pneumonectomy and we have provided evidence for the existence of such cells in human.

Identification of a novel subset of alveolar type 2 cells enriched in PD-L1 and expanded following pneumonectomy