title: Foxp3+Regulatory T Cell Expression of Keratinocyte Growth Factor Enhances Lung Epithelial Proliferation.
abstract: Repair of the lung epithelium after injury is a critical component for resolution; however, the processes necessary to drive epithelial resolution are not clearly defined. Published data demonstrate that Foxp3+regulatory T cells (Tregs) enhance alveolar epithelial proliferation after injury, and Tregs in vitro directly promote type II alveolar epithelial cell (AT2) proliferation, in part by a contact-independent mechanism. Therefore, we sought to determine the contribution of Treg-specific expression of a growth factor that is known to be important in lung repair, keratinocyte growth factor (kgf). The data demonstrate that Tregs express kgf and that Treg-specific expression of kgf regulates alveolar epithelial proliferation during the resolution phase of acute lung injury and in a model of regenerative alveologenesis in vivo. In vitro experiments demonstrate that AT2 cells cocultured with Tregs lacking kgf have decreased rates of proliferation compared with AT2 cells cocultured with wild-type Tregs. Moreover, Tregs isolated from lung tissue and grown in culture express higher levels of two growth factors that are important for lung repair (kgf and amphiregulin) compared with Tregs isolated from splenic tissue. Lastly, Tregs isolated from human lung tissue can be stimulated ex vivo to induce kgf expression. This study reveals mechanisms by which Tregs direct tissue-reparative effects during resolution after acute lung injury, further supporting the emerging role of Tregs in tissue repair.
authors.affiliation: 1 Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine.|2 Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Catherine F
authors.initials: CF
authors.lastname: Dial
authors.affiliation: 1 Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine.|2 Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Miriya K
authors.initials: MK
authors.lastname: Tune
authors.affiliation: 1 Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine.|3 Center for Airways Disease, and.|2 Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Doerschuk
authors.affiliation: 1 Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine.|2 Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Mock
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019264:Adoptive Transfer; D056809:Alveolar Epithelial Cells / Q000166:cytology* / Q000473:pathology; D066258:Amphiregulin / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002455:Cell Division; D018920:Coculture Techniques; D004167:Diphtheria Toxin / Q000633:toxicity; D051523:Fibroblast Growth Factor 7 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000032:analysis; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000166:cytology; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011013:Pneumonectomy; D011183:Postoperative Complications / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000145:classification / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D004167:Diphtheria Toxin; C496453:FGF7 protein, human; C496454:Fgf7 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D008070:Lipopolysaccharides; D051523:Fibroblast Growth Factor 7
keywords: Foxp3; acute lung injury; alveolar epithelial repair; keratinocyte growth factor; regulatory T cells