Significance: Idiopathic pulmonary fibrosis and emphysema are leading causes of mortality, but there are no effective therapies. Mutations in telomerase are the most common identifiable risk factor for idiopathic pulmonary fibrosis. They also predispose to severe emphysema in smokers, occurring at a frequency similar to α-1 antitrypsin deficiency. The work shown here points to alveolar stem cell senescence as a driver of these pathologies. Epithelial stem cell failure was associated with secondary inflammatory recruitment and exquisite susceptibility to injury from “second hits.” The findings suggest that efforts to reverse the stem cell failure state directly, rather than its secondary consequences, may be an effective therapy approach in telomere-mediated lung disease.

Acute respiratory distress syndrome (ARDS) causes significant morbidity and mortality each year. There is a paucity of information regarding the mechanisms necessary for ARDS resolution. Foxp3⁺ regulatory T cells (Foxp3⁺ T_reg cells) have been shown to be an important determinant of resolution in an experimental model of lung injury. We demonstrate that intratracheal delivery of endotoxin (lipopolysaccharide) elicits alveolar epithelial damage from which the epithelium undergoes proliferation and repair. Epithelial proliferation coincided with an increase in Foxp3⁺ T_reg cells in the lung during the course of resolution. To dissect the role that Foxp3⁺ T_reg cells exert on epithelial proliferation, we depleted Foxp3⁺ T_reg cells, which led to decreased alveolar epithelial proliferation and delayed lung injury recovery. Furthermore, antibody-mediated blockade of CD103, an integrin, which binds to epithelial expressed E-cadherin decreased Foxp3⁺ T_reg numbers and decreased rates of epithelial proliferation after injury. In a non-inflammatory model of regenerative alveologenesis, left lung pneumonectomy, we found that Foxp3⁺ T_reg cells enhanced epithelial proliferation. Moreover, Foxp3⁺ T_reg cells co-cultured with primary type II alveolar cells (AT2) directly increased AT2 cell proliferation in a CD103-dependent manner. These studies provide evidence of a new and integral role for Foxp3⁺ T_reg cells in repair of the lung epithelium.