Regulatory T cells protect against aberrant remodeling in a mouse model of pulmonary fibrosis

Aditi Murthy, Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States; PENN-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States.
Luis R. Rodríguez, Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States; PENN-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States; Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, United States.
Willy Roque Barboza, Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States; PENN-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States.
Yaniv Tomer, Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States; PENN-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States.
Sarah Bui, Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States; PENN-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States.
Paige Carson, Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States; PENN-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States.
Thalia Dimopoulos, Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States; PENN-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States.
Swati Iyer, Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States; PENN-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States.
Katrina Chavez, Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States; PENN-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States.
Charlotte H. Cooper, Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States; PENN-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States.
Jeremy B. Katzen, Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States; PENN-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States.
Michael F. Beers, Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States; PENN-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States. Electronic address: mfbeers@pennmedicine.upenn.edu.

Document Type

Journal Article

Publication Date

12-27-2025

Journal

Mucosal immunology

DOI

10.1016/j.mucimm.2025.12.004

Keywords

Alveolar type 2 epithelial cell; Amphiregulin; Lung fibroblast; Lung remodeling; Treg

Abstract

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 (SFTPC). 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 Sftpc 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.

Department

Biochemistry and Molecular Medicine

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