Semaphorin 7a+ Regulatory T Cells Are Associated with Progressive Idiopathic Pulmonary Fibrosis and Are Implicated in Transforming Growth Factor-β1-induced Pulmonary Fibrosis
Semaphorin 7a+ Regulatory T Cells Are Associated with Progressive Idiopathic Pulmonary Fibrosis and Are Implicated in Transforming Growth Factor-β1-induced Pulmonary Fibrosis
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DOI：
10.1164/rccm.201206-1109oc
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发表时间：
2013-01-15
影响因子：
24.7
通讯作者：
Herzog, Erica L.
中科院分区：
文献类型：
--
作者：
Reilkoff, Ronald A.;Peng, Hong;Herzog, Erica L.
理论基础：淋巴细胞与特发性肺纤维化(IPF)的关系日益密切。信号素7a(Sema 7a)参与淋巴细胞活化。目的：明确Sema 7a与IPF中淋巴细胞的关系。方法：我们研究了Sema 7a(+)淋巴细胞在人特发性肺纤维化和肺纤维化模型中的意义。我们确定了Sema 7a在人和小鼠肺和循环中的表达部位，并采用过继转移的方法来确定共表达Sema 7a的淋巴细胞与CD19、CD4、CD19、CD4的相关性。在转化生长因子-β1诱导的小鼠肺纤维化中表达CD25(+)和FoxP3(+)。测量和主要结果：IPF患者肺CD4细胞和循环中的CD4(+)或CD19(+)细胞表达Sema 7a。在进展性IPF患者中，SEMA 7a在CD4(+)细胞和CD4(+)CD25(+)FoxP3(+)调节性T细胞上的表达增加，但在CD19(+)细胞上不表达。在转化生长因子-β1转基因小鼠的肺和脾中，SEMA 7a在表达CD4而不表达CD19的淋巴细胞上表达。表达骨髓来源细胞的SEMA 7a诱导肺纤维化并改变T细胞介质的产生，包括干扰素-γ、IL-4、IL-17A和IL-10。这些效应需要CD4，但不需要CD19。与Sema 7a-CD4(+)CD25(+)FoxP3(+)细胞相比，Sema7a(+)CD4(+)CD25(+)FoxP3(+)细胞IL-10等调节基因表达降低，过继转移这些细胞可诱导肺纤维化和肺重塑。结论：SEMA 7a(+)CD4(+)CD25(+)FoxP3(+)调节性T细胞参与了IPF的发病过程，并诱导肺纤维化。
Rationale: Lymphocytes are increasingly associated with idiopathic pulmonary fibrosis (IPF). Semaphorin 7a (Sema 7a) participates in lymphocyte activation.Objectives: To define the relationship between Sema 7a and lymphocytes in IPF.Methods: We characterized the significance of Sema 7a(+) lymphocytes in humans with IPF and in a mouse model of lung fibrosis caused by lung-targeted, transgenic overexpression of TGF-beta 1. We determined the site of Sema 7a expression in human and murine lungs and circulation and used adoptive transfer approaches to define the relevance of lymphocytes coexpressing Sema7a and the markers CD19, CD4, or CD4(+)CD25(+)FoxP3(+) in TGF-beta 1-induced murine lung fibrosis.Measurements and Main Results: Subjects with IPF show expression of Sema 7a on lung CD4 cells and circulating CD4(+) or CD19(+) cells. Sema 7a expression is increased on CD4(+) cells and CD4(+)CD25(+) FoxP3(+) regulatory T cells, but not CD19(+) cells, in subjects with progressive IPF. Sema 7a is expressed on lymphocytes expressing CD4 but not CD19 in the lungs and spleen of TGF-beta 1 transgenic mice. Sema 7a expressing bone marrow derived cells induce lung fibrosis and alter the production of T-cell mediators, including IFN-gamma, IL-4, IL-17A, and IL-10. These effects require CD4 but not CD19. In comparison to Sema 7a-CD4(+)CD25(+)FoxP3(+) cells, Sema7a(+)CD4(+)CD25(+) FoxP3(+) cells exhibit reduced expression of regulatory genes such as IL-10, and adoptive transfer of these cells induces fibrosis and remodeling in the TGF-beta 1 exposed murine lung.Conclusions: Sema 7a(+)CD4(+)CD25(+)FoxP3(+) regulatory T cells are associated with disease progression in subjects with IPF and induce fibrosis in the TGF-beta 1 exposed murine lung.