Abstract
AbstactDecidual γδΤ (dγδΤ) cells play an essential role during successful pregnancy; however, the residence and polarization of γδΤ cells in decidua remain unclear. In this study, we observed higher levels of receptor activator for nuclear factor-κ B ligand (RANKL) on decidual stromal cells (DSCs), and its receptor RANK on dγδΤ cells in decidua from normal pregnancy compared with patients with recurrent spontaneous abortion (RSA). RANKL expressed by DSCs can induce the polarization of peripheral blood γδΤ (pγδΤ) and dγδΤ cells to Foxp3 + γδΤ cells, and upregulate the expression of transforming growth factor (TGF)-β1. This process is mediated through activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In addition, RANKL promotes the adhesion of dγδΤ cells to DSCs in vitro, which is associated with the upregulation of ICAM-1 and VCAM-1 on DSCs and integrins on dγδΤ cells. RANKL knockout leads to the decreased numbers of uterus total γδΤ cells, Foxp3+γδΤ cells and the expression of TGF-β1, and the increased pregnancy loss in mice. These results suggest that RANKL is a pivotal regulator of maternal-fetal tolerance by triggering the polarization and residence of TGF-β1-producing Foxp3+γδΤ cells in early pregnancy. The abnormal low level of RANKL/RANK results in pregnancy loss because of the dialogue disorder between DSCs and dγδΤ cells. This observation provides a scientific basis on which a potential marker can be detected to early warning of pregnancy loss.
Highlights
Decidual immune cell (DIC), one of the major components at the maternal-fetal interface, is critical in the induction of maternal immune tolerance to fetal alloantigen during pregnancy[1,2,3]
We focus on the interaction between decidual stromal cells (DSCs)-derived RANKL and RANK expressed on Decidual γδ T (dγδ T) cells and reveal their role in the maintenance of early pregnancy and recurrent spontaneous abortion (RSA)
Here we demonstrated that, at the maternal-fetal interface, DSC-derived RANKL promotes the polarization of dγδ T cells into Foxp3+ regulatory γδ T cells and elevates transforming growth factor (TGF)-β1 production by activating NF-κB pathway
Summary
Decidual immune cell (DIC), one of the major components at the maternal-fetal interface, is critical in the induction of maternal immune tolerance to fetal alloantigen during pregnancy[1,2,3]. Γδ[1, 2, 17, 22], follicular helper (FH), and regulatory (reg) cells are characterized by its capacity to produce interferon (IFN)-γ, interleukin (IL)-4, IL-17, IL-22, Th2-cell-associated cytokines (including IL-4 and IL-10), and transforming growth factor (TGF)-β, respectively. Accumulating evidence showed that dγδ T cells have a tendency to secrete immunosuppressive cytokines, especially TGF-β and IL-10 at maternal-fetal interface[7,16,17].
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