Decidual vascular endothelial cells promote maternal–fetal immune tolerance by inducing regulatory T cells through canonical Notch1 signaling

Abstract

Adaptation of the maternal immune response to accommodate the semiallogeneic fetus is necessary for pregnancy success. However, the mechanisms by which the fetus avoids rejection despite expression of paternal alloantigens remain incompletely understood. Regulatory T cells (Treg cells) are pivotal for maintaining immune homeostasis, preventing autoimmune disease and fetus rejection. In this study, we found that maternal decidual vascular endothelial cells (DVECs) sustained Foxp3 expression in resting Treg cells in vitro. Moreover, under in vitro Treg cell induction condition with agonistic antibodies and transforming growth factor (TGF)-β, DVECs promoted Treg cell differentiation from non-Treg conventional T cells. Consistent with the promotion of Treg cell maintenance and differentiation, Treg cell-associated gene expression such as TGF-β, Epstein-Barr-induced gene-3, CD39 and glucocorticoid-induced tumor necrosis factor receptor was also increased in the presence of DVECs. Further study revealed that DVECs expressed Notch ligands such as Jagged-1, Delta-like protein 1 (DLL-1) and DLL-4, while Treg cells expressed Notch1 on their surface. The effects of DVECs on Treg cells was inhibited by siRNA-induced knockdown of expression of Jagged-1 and DLL-1 in DVECs. Downregulation of Notch1 in Treg cells using lentiviral shRNA transduction decreased Foxp3 expression in Treg cells. Adoptive transfer of Notch1-deficient Treg cells increased abortion rate in a murine semiallogeneic pregnancy model. Taken together, our study suggests that maternal DVECs are able to maintain decidual Treg cell identity and promote Treg cell differentiation through activation of Notch1 signal pathway in Treg cells and subsequently inhibit the immune response against semiallogeneic fetuses and preventing spontaneous abortion.

TGFb1 suppresses the activation of distinct dNK subpopulations in preeclampsia

“…Treg cells appear to play a key role suppressing activity of specific dNK subpopulations. However, we do not exclude the contribution of other cells at the maternal-fetal interface, including various immune and non-immune cells, necessary for normal dNK activity [[39], [40], [41], [42]]. In addition, distinct regulatory mechanisms may underlie decidual immunosuppression since dNK subsets responded differently to TGFb1 signalling.…”

Distinct T and NK cell populations may serve as immune correlates of protection against symptomatic pandemic influenza A(H1N1) virus infection during pregnancy

“…NK and T cells from pregnant women had reduced production of interferon (IFN)-γ and macrophage inflammatory protein (MIP)-1β [ 10 , 11 ]. Recently, CD8 + effector cells and T regulatory cells (Tregs) at the fetal-maternal interface were implicated as modulators of fetal-immune tolerance and antiviral immunity [ 12 – 14 ].…”

Mesenchymal Stromal Cells: What Is the Mechanism in Acute Graft-Versus-Host Disease?

“…The use of adenosine signaling inhibitors to boost tumor immune responses is an area of active clinical investigation [ 69 ]. Like IDO, CD39 is known to promote tolerance at the maternal–fetal interface [ 70 ].…”