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

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 naive 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.