PDGF-Producing CD4+ Foxp3+ Regulatory T Lymphocytes Promote Lung Fibrosis.

RATIONALE: 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 counterparts (T regs) remains to be determined. OBJECTIVES: To elucidate the contribution of T regs in a mouse model of lung fibrosis induced by silica particles. METHODS: Lung T regs and T eff purified from silica-treated Foxp3-GFP transgenic mice were co-cultured with naive lung fibroblasts or transferred in the lung of healthy mice. DEREG mice which express the diphtheria toxin receptor (DTR) under the control of the foxp3 gene were used to deplete T regs during fibrogenesis. MEASUREMENTS AND MAIN RESULTS: CD4(+) Foxp3(+) T regs were persistently recruited in the lungs in response to silica. T reg accumulation paralleled the establishment of pulmonary immunosuppression and fibrosis. T regs highly expressed the 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 regs were completely 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 and IL-4-driven pulmonary fibrogenesis, further demonstrating that T regs control T eff functions during inflammatory fibrosis. CONCLUSIONS: Our study indicates that T regs contribute to lung fibrosis by stimulating fibroblasts through the secretion of PDGF-B in non-inflammatory conditions and regulate detrimental T eff activities during inflammation-related fibrosis.

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Lo Re, S., Lecocq, M., Uwambayinema, F., Yakoub, Y., Delos, M., Demoulin, J. B., Lucas, S., Sparwasser, T., Renauld, J.-C., Lison, D., & Huaux, F. (2011). PDGF-Producing CD4+ Foxp3+ Regulatory T Lymphocytes Promote Lung Fibrosis. American Journal of Respiratory and Critical Care Medicine, 184(11), 1270-1281. https://doi.org/10.1164/rccm.201103-0516OC (Original work published 2011)