Murthy Aditi, Rodríguez Luis R, Barboza Willy Roque, Tomer Yaniv, Bui Sarah, Carson Paige, Dimopoulos Thalia, Iyer Swati, Chavez Katrina, Cooper Charlotte H, Katzen Jeremy B, Beers Michael F
Pulmonary, Allergy, and Critical Care Division, Department of Medicine; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.
PENN-CHOP Lung Biology Institute; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA 19104.
bioRxiv. 2025 Jul 5:2025.07.02.662777. doi: 10.1101/2025.07.02.662777.
Regulatory T (Treg) cells are well recognized for their role in immune regulation; however, their role in tissue regeneration is not fully understood. This study demonstrates such a role of Tregs in a published preclinical murine model of spontaneous pulmonary fibrosis (PF) expressing a human PF related mutation in the Surfactant Protein-C (SP-C) gene ( ). Genetic crosses of SP-C mice with Foxp3 and Foxp3 lines were utilized to study Treg behavior during PF development. We found that FoxP3+Tregs accumulate during the transition from inflammation to fibrogenesis, peaking at 21-28 days after mutant induction localizing to both perivascular and distal fibrotic lung regions. Diphtheria toxin mediated ablation of Tregs at 17 days worsened fibrosis and increased levels of TGFβ and inflammatory cytokines. Tregs expressed Th2 markers (Gata3+) and elaborated factors including amphiregulin (Areg) and Osteopontin (Spp1). Reductionist experiments showed that lung Tregs enhanced organoid formation when co-cultured with alveolar epithelial cells and adventitial fibroblasts, an effect size mimicked using Areg and Spp1 in combination. Our findings demonstrate that immune-mesenchymal-epithelial signaling crosstalk is present in the distal lung wherein Tregs play a protective role by limiting fibrosis and promoting tissue repair, highlighting their broader function beyond immune modulation in lung injury.
调节性T（Treg）细胞在免疫调节中的作用已得到充分认可；然而，它们在组织再生中的作用尚未完全明确。本研究在已发表的一种临床前小鼠自发性肺纤维化（PF）模型中证实了Treg细胞的这一作用，该模型在表面活性蛋白C（SP-C）基因中表达一种与人类PF相关的突变。利用携带Foxp3和Foxp3系的SP-C小鼠进行遗传杂交，以研究PF发展过程中Treg细胞的行为。我们发现，FoxP3+Treg细胞在从炎症向纤维化转变的过程中积累，在突变诱导后21 - 28天达到峰值，定位于血管周围和远端纤维化肺区域。在第17天用白喉毒素介导Treg细胞消融会加重纤维化，并增加TGFβ和炎性细胞因子的水平。Treg细胞表达Th2标志物（Gata3+），并产生包括双调蛋白（Areg）和骨桥蛋白（Spp1）在内的因子。简化实验表明，肺Treg细胞与肺泡上皮细胞和外膜成纤维细胞共培养时可增强类器官形成，联合使用Areg和Spp1可模拟这种效应大小。我们的研究结果表明，远端肺中存在免疫-间充质-上皮信号串扰，其中Treg细胞通过限制纤维化和促进组织修复发挥保护作用，突出了它们在肺损伤中除免疫调节之外的更广泛功能。
