Placental endovascular extravillous trophoblasts (enEVTs) educate maternal T‐cell differentiation along the maternal‐placental circulation

Abstract

Objectives: During human pregnancy, the endothelial cells of the uterine spiral arteries (SPA) are extensively replaced by a subtype of placental trophoblasts, endovascular extravillous trophoblasts (enEVTs), thus establishing a placental-maternal circulation. On this pathway, foetus-derived placental villi and enEVTs bath into the maternal blood that perfuses along SPA being not attacked by the maternal lymphocytes. We aimed to reveal the underlying mechanism of such immune tolerance. Methods:In situ hybridization, immunofluorescence, ELISA and FCM assay were performed to examine TGF-β1 expression and distribution of regulatory T cells (Tregs) along the placental-maternal circulation route. The primary enEVTs, interstitial extravillous trophoblasts (iEVTs) and decidual endothelial cells (dECs) were purified by FACS, and their conditioned media were collected to treat naïve CD4 + T cells. Treg differentiation was measured by FLOW and CFSE assays. Results:We found that enEVTs but not iEVTs or dECs actively produced TGF-β1. The primary enEVTs significantly promoted naïve CD4 + T-cell differentiation into immunosuppressive FOXP3 + Tregs, and this effect was dependent on TGF-β1. In recurrent spontaneous abortion (RSA) patients, an evidently reduced proportion of TGF-β1producing enEVTs and their ability to educate Tregs differentiation were observed. Conclusions:Our findings demonstrate a unique immune-regulatory characteristic of placental enEVTs to develop immune tolerance along the placental-maternal circulation. New insights into the pathogenesis of RSA are also suggested.

Role of Transforming Growth Factor-β1 in Regulating Fetal-Maternal Immune Tolerance in Normal and Pathological Pregnancy

“…Treatment with vasoactive intestinal peptide (VIP) in a miscarriage-prone mouse model (CBA/J×DBA/2) can regulate the endocytosis of maternal macrophages and promote the expression of TGF-b1 at the implantation site of the mouse, significantly increasing the number of implant points (97). In addition, Ma et al (98) found that endovascular extravillous trophoblasts (enEVTs) actively produced TGF-b1, and primary enEVTs promoted the differentiation of naive CD4 + T cells into immunosuppressive Tregs in a TGF-b1-dependent manner. The proportion of TGF-b1-producing enEVTs and their ability to educate Tregs differentiation were significantly reduced in RSA patients.…”

“…In addition, Ma et al. ( 98 ) found that endovascular extravillous trophoblasts (enEVTs) actively produced TGF-β1, and primary enEVTs promoted the differentiation of naive CD4 + T cells into immunosuppressive Tregs in a TGF-β1-dependent manner. The proportion of TGF-β1-producing enEVTs and their ability to educate Tregs differentiation were significantly reduced in RSA patients.…”

Crosstalk Between Trophoblasts and Decidual Immune Cells: The Cornerstone of Maternal-Fetal Immunotolerance

“…Similar result was obtained in another experiment that HLA-G + EVTs co-cultured with matched CD4 + T cells led to the augment of CD4 + CD25 HI FOXP3 + CD45RA + resting Treg cells (97). Recently, further research has shown that endovascular extravillous trophoblasts (enEVTs), but not interstitial extravillous trophoblasts (iEVTs), were capable of promoting the differentiation of naïve CD4 + T cells into immunosuppressive Treg cells in a TGF-β1-dependent manner, establishing immune tolerance along the placental-maternal circulation (98). As mentioned earlier, IL-35 is also an important regulator of Treg cell function and differentiation.…”

The Role of Immune Cells in Recurrent Spontaneous Abortion

“…In addition, Treg differentiation was also achieved by endovascular extravillous trophoblasts (enEVTs), which are capable of establishing placental-maternal circulation during human pregnancy [ 133 ]. However, a recent study observed that a significant decrease in the percentage of enEVTs was associated with the failure of Treg cell differentiation, leading to insufficient spiral artery remodeling in RSA patients [ 134 ].…”