Upregulation of CD81 in trophoblasts induces an imbalance of Treg/Th17 cells by promoting IL-6 expression in preeclampsia
Upregulation of CD81 in trophoblasts induces an imbalance of Treg/Th17 cells by promoting IL-6 expression in preeclampsia
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先兆子痫中滋养层细胞 CD81 上调通过促进 IL-6 表达诱导 Treg/Th17 细胞失衡
DOI：
10.1038/s41423-018-0186-9
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发表时间：
2019-03-01
影响因子：
24.1
通讯作者：
Hu, Yali
中科院分区：
文献类型：
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作者：
Ding, Hailin;Dai, Yimin;Hu, Yali
母体免疫耐受紊乱被认为是子痫前期(Preeclampsia，PE)的重要病理机制之一，其中炎症限制性调节性T细胞(Tregs)和炎症介质Th17细胞之间的失衡起着至关重要的作用。在此之前，我们曾报道滋养层细胞(胎儿成分)中Tetraspannin CD81的异常上调参与了PE的发病。然而，CD81作为一种潜在的免疫调节分子，是否通过干扰母体免疫系统的平衡来诱导PE，目前尚不清楚。因此，我们研究了母亲滋养层细胞CD81表达上调与Treg/Th17细胞失衡的关系。在此，我们发现PE患者滋养层细胞CD81表达上调的同时，胎盘母体基板(胎盘母体侧)和外周血中Treg细胞减少，Th17细胞增加。CD81高表达的滋养层细胞株HTR-8体外培养的幼稚T细胞可促进T细胞向Th17细胞分化，减少Tregs的形成，这依赖于CD81诱导滋养细胞IL-6的旁分泌信号。在CD81诱导的PE大鼠模型中，我们发现T细胞向Th17细胞分化的显著转变，IL-6抗体的应用减轻了PE表型和Treg/Th17细胞的失衡。这些结果明确了涉及滋养细胞来源的CD81、IL-6和母体Treg/Th17细胞在PE发病机制中的重要调节级联反应，并提出了基于CD81和IL-6下调的新的治疗方法来预防人类PE。
The disturbance of maternal immune tolerance to a semiallogeneic fetus is recognized as one of the key pathologies of preeclampsia (PE), in which an imbalance between the inflammation-limiting regulatory T cells (Tregs) and the inflammation-mediating Th17 cells plays an essential role. Previously, we reported that the abnormal upregulation of tetraspannin CD81 in trophoblast cells (fetal component) participated in the pathogenesis of PE. However, as one of the potential immune regulatory molecules, whether CD81 induces PE by interfering with the balance of the maternal immune system has not yet been clarified. Thus, we investigated the relationship between the upregulation of CD81 in trophoblast cells and the imbalance of Treg and Th17 cells in mothers. Here, we demonstrated that upregulation of CD81 in trophoblast cells was accompanied by a decrease in Treg cells and an increase in Th17 cells in both the basal plate (placental maternal side) and peripheral blood of patients with PE. In vitro culture of naïve T cells with medium from the CD81-overexpressing trophoblast cell line HTR-8 resulted in enhanced differentiation of T cells into Th17 cells and decreased the formation of Tregs, which was dependent on the paracrine signaling of IL-6 in trophocytes, induced by CD81. In a CD81-induced PE rat model, we found a significant shift of T cell differentiation towards Th17 cells, and administration of IL-6 antibody mitigated the PE phenotype and the imbalance of the Treg/Th17 cells. These results define a vital regulatory cascade involving trophocyte-derived CD81, IL-6, and maternal Treg/Th17 cells in the pathogenesis of PE and suggests new therapeutic approaches based on CD81 and IL-6 downregulation to prevent human PE.