Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease
Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease
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DOI：
10.4049/jimmunol.1202144
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发表时间：
2013-02-01
影响因子：
4.4
通讯作者：
Hartl, Dominik
中科院分区：
文献类型：
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作者：
Rieber, Nikolaus;Brand, Alina;Hartl, Dominik
铜绿假单胞菌在囊性纤维化（CF）患者中持续存在，并推动CF肺病进展。铜绿假单胞菌有效地激活先天免疫系统，主要通过病原体相关的分子模式，如鞭毛蛋白介导。然而，宿主不能有效地根除这种鞭毛细菌。潜在的免疫学机制尚未完全了解。骨髓源性抑制细胞（MDSC）是在癌症和促炎微环境中产生的先天性免疫细胞，并且能够抑制T细胞应答。我们假设铜绿假单胞菌诱导MDSC逃避T细胞免疫。在这篇文章中，我们证明了粒细胞MDSC在慢性感染铜绿假单胞菌的CF患者中积累，并与CF肺病活动相关。鞭毛化的铜绿假单胞菌培养物上清液诱导MDSC的产生，该作用1）被纯化的鞭毛蛋白剂量依赖性地模拟，2）使用鞭毛蛋白缺陷的铜绿假单胞菌细菌显著降低，和3）对应于体外和体内MDSC上的TLR 5表达。纯化的鞭毛蛋白和鞭毛化的铜绿假单胞菌诱导的MDSC表型与先前描述的MDSC诱导细胞因子GM-CSF的表型不同，其特征在于MDSC表面上的趋化因子受体CXCR 4的上调。在功能上，铜绿假单胞菌感染的CF患者离体分离以及鞭毛蛋白或铜绿假单胞菌在体外产生的MDSC以剂量依赖性方式有效抑制多克隆T细胞增殖并调节Th 17应答。这些研究表明，鞭毛蛋白诱导MDSC的产生，并表明铜绿假单胞菌使用这种机制来破坏CF和其他铜绿假单胞菌相关慢性肺病中T细胞介导的宿主防御。免疫学杂志，2013，190：1276-1284。
Pseudomonas aeruginosa persists in patients with cystic fibrosis (CF) and drives CF lung disease progression. P. aeruginosa potently activates the innate immune system, mainly mediated through pathogen-associated molecular patterns, such as flagellin. However, the host is unable to eradicate this flagellated bacterium efficiently. The underlying immunological mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells generated in cancer and proinflammatory microenvironments and are capable of suppressing T cell responses. We hypothesized that P. aeruginosa induces MDSCs to escape T cell immunity. In this article, we demonstrate that granulocytic MDSCs accumulate in CF patients chronically infected with P. aeruginosa and correlate with CF lung disease activity. Flagellated P. aeruginosa culture supernatants induced the generation of MDSCs, an effect that was 1) dose-dependently mimicked by purified flagellin protein, 2) significantly reduced using flagellin-deficient P. aeruginosa bacteria, and 3) corresponded to TLR5 expression on MDSCs in vitro and in vivo. Both purified flagellin and flagellated P. aeruginosa induced an MDSC phenotype distinct from that of the previously described MDSC-inducing cytokine GM-CSF, characterized by an upregulation of the chemokine receptor CXCR4 on the surface of MDSCs. Functionally, P. aeruginosa-infected CF patient ex vivo-isolated as well as flagellin or P. aeruginosa in vitro-generated MDSCs efficiently suppressed polyclonal T cell proliferation in a dose-dependent manner and modulated Th17 responses. These studies demonstrate that flagellin induces the generation of MDSCs and suggest that P. aeruginosa uses this mechanism to undermine T cell-mediated host defense in CF and other P. aeruginosa-associated chronic lung diseases. The Journal of Immunology, 2013, 190: 1276-1284.