title: Platelet-derived growth factor-producing CD4+ Foxp3+ regulatory T lymphocytes promote lung fibrosis.
abstract: BACKGROUND
  There is evidence that CD4(+) effector T lymphocytes (T eff) participate in the development of lung fibrosis, but the role of their CD4(+) regulatory T-cell (T reg) counterparts remains to be determined.
  
  
  OBJECTIVE
  To elucidate the contribution of T reg cells in a mouse model of lung fibrosis induced by silica (SiO(2)) particles.
  
  
  METHODS
  Lung T reg and T eff cells purified from SiO(2)-treated Foxp3-GFP transgenic mice were cocultured with naive lung fibroblasts or transferred to the lungs of healthy mice. DEREG mice, which express the diphtheria toxin receptor under the control of the foxp3 gene, were used to deplete T reg cells during fibrogenesis.
  
  
  RESULTS
  CD4(+) Foxp3(+) T reg cells were persistently recruited in the lungs in response to SiO(2). T reg accumulation paralleled the establishment of pulmonary immunosuppression and fibrosis. T reg cells highly expressed platelet-derived growth factor (PDGF)-B via a TGF-β autocrine signaling pathway, directly stimulated fibroblast proliferation in vitro, and increased lung collagen deposition upon transfer in the lung of naive mice. The direct profibrotic effects of T reg cells were abolished by the inhibitor of the PDGF-B/TGF-β signaling pathway, imatinib mesylate. Neutralization of T reg-immunosuppressive activity resulted in enhanced accumulation of T eff cells and IL-4-driven pulmonary fibrogenesis, further demonstrating that T reg cells control T eff cell functions during inflammatory fibrosis.
  
  
  CONCLUSIONS
  Our study indicates that T reg cells contribute to lung fibrosis by stimulating fibroblasts through the secretion of PDGF-B in noninflammatory conditions and regulate detrimental T eff cell activities during inflammation-related fibrosis.
authors.affiliation: Louvain Centre for Toxicology and Applied Pharmacology, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lo Re
authors.forename: Marylène
authors.initials: M
authors.lastname: Lecocq
authors.forename: Francine
authors.initials: F
authors.lastname: Uwambayinema
authors.forename: Yousof
authors.initials: Y
authors.lastname: Yakoub
authors.forename: Monique
authors.initials: M
authors.lastname: Delos
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Demoulin
authors.forename: Sophie
authors.initials: S
authors.lastname: Lucas
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Renauld
authors.forename: Dominique
authors.initials: D
authors.lastname: Lison
authors.forename: François
authors.initials: F
authors.lastname: Huaux
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D005434:Flow Cytometry / Q000379:methods; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010982:Platelet-Derived Growth Factor / Q000276:immunology* / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; D010982:Platelet-Derived Growth Factor