Platelet-Derived Growth Factor-Producing CD4+ Foxp3+ Regulatory T Lymphocytes Promote Lung Fibrosis
Platelet-Derived Growth Factor-Producing CD4+ Foxp3+ Regulatory T Lymphocytes Promote Lung Fibrosis
复制标题
DOI：
10.1164/rccm.201103-0516oc
复制
发表时间：
2011-12-01
影响因子：
24.7
通讯作者：
Huaux, Francois
中科院分区：
文献类型：
--
作者：
Lo Re, Sandra;Lecocq, Marylene;Huaux, Francois
基本原理：有证据表明CD 4（+）效应T淋巴细胞（Teff）参与了肺纤维化的发展，但其CD 4（+）调节性T细胞（Treg）对应物的作用仍有待确定。目的：目的：探讨T reg细胞在二氧化硅（SiO2）颗粒诱导小鼠肺纤维化模型中的作用。方法：从经SiO2处理的Foxp 3-GFP转基因小鼠中纯化的肺T reg和T eff细胞与幼稚肺成纤维细胞共培养或转移到健康小鼠肺中。DEREG小鼠，表达白喉毒素受体的foxp 3基因的控制下，被用来消耗T reg细胞在fibrogenesis. Measures和主要结果：CD 4（+）Foxp 3（+）T reg细胞持续招募在肺部SiO2。T reg的积累促进了肺免疫抑制和纤维化的建立。T reg细胞通过TGF-β自分泌信号通路高度表达血小板衍生生长因子（PDGF）-B，在体外直接刺激成纤维细胞增殖，并在转移到未处理小鼠肺中后增加肺胶原沉积。T reg细胞的直接促纤维化作用被PDGF-B/TGF-β信号通路抑制剂甲磺酸伊马替尼消除。T reg免疫抑制活性的中和导致T eff细胞的积累和IL-4驱动的肺纤维化的增强，进一步证明T reg细胞在炎性纤维化期间控制T eff细胞功能。我们的研究表明，T reg细胞通过分泌PDGF-Bin刺激成纤维细胞，在非炎症条件下促进肺纤维化，并在炎症期间调节有害的T eff细胞活性。纤维化相关
Rationale: There is evidence that CD4(+) effector T lymphocytes (T eff) participate in the development of lung fibrosis, but the role of their CD4(+) regulatoryT-cell (Treg) counterparts remains to be determined. Objectives: To elucidate the contribution of T reg cells in a mouse model of lung fibrosis induced by silica (SiO2) particles.Methods: Lung T reg and T eff cells purified from SiO2-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.Measurements and Main Results: CD4(+) Foxp3(+) T reg cells were persistently recruited in the lungs in response to SiO2. 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-beta 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-beta 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-Bin noninflammatory conditions and regulate detrimental T eff cell activities during inflammation-related fibrosis.