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Upregulation of CD81 in trophoblasts induces an imbalance of Treg/Th17 cells by promoting IL-6 expression in preeclampsia

Cellular & Molecular Immunology volume 16, pages 302–312 (2019)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81571462, 81600353, and 81701472), Jiangsu Provincial Key Medical Center (YXZXB2016004), Jiangsu Biobank of Clinical Resources (BM2015004), and Jiangsu Province Grant for Science and Technology (BK20161106). We would like to thank our patients and our colleagues at the Biobank of Nanjing for the donation and collection of placental tissues and blood samples in this study.

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  1. These authors contributed equally to this work: Hailin Ding, Yimin Dai.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Nanjing University Medical School, 210008, Nanjing, China

    Hailin Ding, Yimin Dai, Yi Lei, Zhiyin Wang, Dan Liu, Li Shen, Ning Gu, Mingming Zheng, Xiangyu Zhu, Guangfeng Zhao & Yali Hu

  2. Department of Laboratory Medicine, Jiangsu Key Laboratory for Molecular Medicine, Nanjing University Medical School, 210008, Nanjing, China

    Ruotian Li

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  1. Hailin Ding
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Contributions

H.D. and Y.D designed and performed the experiments, data analysis, and manuscript drafting. Y.L. and Z.W. helped to construct the PE rat model and performed part of the flow cytometry analysis. D.L. and N.G. analyzed data and drew the graphs. R.L. and M.Z. summarized the data and wrote the manuscript. L.S. and X.Z designed the study and collected clinical samples. G.Z. and Y.H. planned and supervised this study. All authors have approved the final version.

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Correspondence to Guangfeng Zhao or Yali Hu.

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Ding, H., Dai, Y., Lei, Y. et al. Upregulation of CD81 in trophoblasts induces an imbalance of Treg/Th17 cells by promoting IL-6 expression in preeclampsia. Cell Mol Immunol 16, 302–312 (2019). https://doi.org/10.1038/s41423-018-0186-9

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