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. 2023 Jul 17;133(14):e170505. doi: 10.1172/JCI170505

Figure 2. Mechanisms of Treg-mediated lung parenchymal tissue protection and repair.

Figure 2

Tregs exert distinct functions to provide tissue protection and promote repair of the epithelial, endothelial, and mesenchymal compartments following infection-induced lung injury. Following lung injury, for example from influenza A virus (IAV) infection, signals from activated immune cells and damaged epithelial cells (e.g., IL-18 and IL-33) bind to their receptors on Tregs and drive Treg production of pro-epithelial growth factors (e.g., AREG and KGF) that signal to epithelial and Col14a1+ mesenchymal cells to promote epithelial regeneration. NOTCH4 regulates this axis in Tregs. The role of Tregs in modulating the population of KRT8+ transitional epithelial cells — also known as pre-alveolar type 1 transitional cell state (PATS), alveolar differentiation intermediate (ADI), damage-associated transient progenitors (DATPs), and intermediate alveolar epithelial cells (AECints) — remains unclear. Tregs also generate pro-endothelial growth factors such as VEGF that promote the regeneration of alveolar capillary endothelial cells (ECs), including those expressing carbonic anhydrase 4 (CAR4) and the endothelial tip cell markers VEGFR2, NRP1, and APLN. Tregs also decrease fibroproliferation by decreasing signaling along the CXCL12/CXCR4 axis to limit collagen deposition by bone marrow–derived collagen-producing cells. AT1 cell, alveolar epithelial type 1 cell; AT2 cell, alveolar epithelial type 2 cell.