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• W2316406581 abstract "Regulatory T cells (Treg) accumulate at the maternal–fetal interface during pregnancy in both human and mice to control detrimental inflammatory responses, which could lead to the rejection of placental and fetal tissues.1, 2 Previous studies suggested that the increase of Treg in decidual tissue is due to the local expansion as well as a selective recruitment of Treg to the maternal–fetal interface.2, 3 To enter decidual tissue, T cells have to adhere to decidual vascular endothelial cells (dVEC) and transmigrate across the endothelial cell (EC) layer. In this issue of ICB, Yao et al.4 demonstrate that in the presence of TGFβ, dVEC stabilize FOXP3+ Treg in an in vitro co-culture system of dVEC and decidual T cells. Thus, the adhesion of T cells to dVEC and subsequent extravasation into decidual tissue may provide a window of opportunity for dVEC to skew T cell differentiation and promote local immune tolerance. Yao et al. further demonstrate that through the expression of Notch1 ligands (Jagged1 and DDL1), dVEC activate Notch1 signaling in Treg and enhance their suppressive function (shown in Figure 1). Adoptive transfer of Notch1 siRNA-transduced Treg resulted in increased placental IFNγ and TNFα expression and increased fetal resorption rates, emphasizing the role of Treg and Notch1 signaling in an in vivo pregnancy model. Besides invading extravillous trophoblasts (EVT) that are found in and in close proximity to the spiral arteries in the placenta, decidual macrophages (dMφ) and decidual stromal cells are the main sources of TGFβ in decidual tissue.3, 5 Thus, these cells influence the microenvironment at the maternal–fetal interface by secretion of TGFβ alone or assist dVEC to sustain Treg function. TGFβ is a powerful regulator of immune cells and was shown to directly induce Treg, inhibit antigen presenting cells as well as convert natural killer (NK) cells into a decidual NK-like phenotype.5 EVT were shown to directly enhance the proportion of FOXP3+ Treg during in vitro co-culture.3 Similar to TGFβ, Notch receptor–ligand interactions and the subsequent signaling pathways have a wide variety of downstream effects on T cell and Treg differentiation. Notch receptor–ligand interactions were specifically shown to balance Th17 and Treg responses, increase the sensitivity of effector T cells to Treg-mediated suppression6 and enhance priming of naive T cells.7 Thus, TGFβ and Notch1 provide multiple and possibly redundant mechanisms to support Treg accumulation in decidua and create a tolerogenic immune environment that allows the growth of allogeneic placental and fetal tissues. Spiral arteries and their EC layer undergo dramatic changes in early pregnancy. Remodeled spiral arteries provide a low-pressure blood flow to the intervillous space and enhance nutrient and gas exchange to the fetus. In species with hemochorial placentation, including humans and mice, spiral artery remodeling involves leukocyte recruitment, invasion of trophoblasts and loss of vascular smooth muscle cells and endothelium, which are replaced by endovascular trophoblasts.8, 9 In mice, migrating trophoblasts were first observed at gestational day (GD) 6.5, whereas at GD 9.5, trophoblast breached the endothelium, entered the vascular lumens and appeared to occlude some vessels as described for human spiral arteries.9 This study uses dVEC at GD 14.5, when trophoblast invasion and spiral artery remodeling are well established. Thus, it provides evidence that remodeled arteries and dVEC sustain Treg function, and preferentially promote immune tolerance. The infiltration of trophoblasts into spiral arteries and their potential to replace the EC layer may add an additional level of control in modulation of immune cells during extravasation into decidua. Investigation into dVEC and effects of EVT infiltration into the spiral arteries at different days of gestation (e.g., before and after spiral artery remodeling is completed) may provide further insight into how dVEC contribute to the unusual dynamics of leukocyte accumulation in decidual tissue (e.g., high proportion of decidual NK in early pregnancy and a later increase in decidual T cells). This will be of especially high interest for studies on pre-eclampsia, a disease of pregnancy characterized by impaired spiral artery remodeling. Impaired spiral artery remodeling leads to complications in the blood flow in the placenta, ischemia re-perfusion injury and oxidative stress of the villi. A lack of endothelium adjustment and diminished EVT invasion of the arteries could also distort the influx of immune cells. In addition, a failure of dVEC to stabilize Treg function and increased immune activation during pre-eclampsia may exacerbate inflammation and worsen disease. In a model for organ transplantation, EC were shown to selectively amplify both pro-inflammatory Th17 cells and FOXP3+ Treg under pro-inflammatory conditions.10 In this case, allogeneic EC were used and that may not be representative for the maternal–fetal interface. However, it does illustrate that EC at the time of T cell adhesion and extravasation through the EC layer provides tight interaction and an opportunity for the EC to influence T cell function as was demonstrated by Yao et al. Under the influence of pro-inflammatory factors, EC also upregulate major histocompatibiliy complex (MHC) expression, express adhesion molecules and guide immune cells into tissues. A previous study suggested that the absence of secretion of key chemokines (Cxcl9 and Ccl5) by decidual stromal cells prevent the influx of T cells into the decidua in healthy murine gestation.11 However, during infections T cells were shown to infiltrate decidua but were less able to clear infections in placenta compared to other tissues.12 Modulation of T cells during interaction and with dVEC as shown by Yao et al., and the influence of the immune suppressive decidual microenvironment may be responsible for diminishing T effector function and preventing fetal rejection but may also impair immunity to infections. Although many of the previous comments are speculative, the key finding of this paper that dVEC assist Treg influx and stabilization merits further investigation. A focus on the role that dVEC play in regulating immune cell composition at the maternal–fetal interface in healthy as well as complicated pregnancies will be of key importance for understanding the etiology of severe pregnancy syndromes such as pre-eclampsia. The authors declare no conflict of interest. Decidual endothelium and Notch1 assist TGFβ to increase Treg at the maternal–fetal interface." @default.
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• W2316406581 date "2016-03-29" @default.
• W2316406581 modified "2023-09-27" @default.
• W2316406581 title "Decidual endothelium, Notch1 and TGF <i>β</i> , gatekeepers for Treg accumulation at the maternal–fetal interface" @default.
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• W2316406581 doi "https://doi.org/10.1038/icb.2016.23" @default.
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