Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, 200011, Shanghai, People's Republic of China.
Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, 200011, Shanghai, People's Republic of China.
Cell Death Dis. 2019 Feb 8;10(2):113. doi: 10.1038/s41419-019-1380-0.
Decidual 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.
蜕膜 γδΤ（dγδΤ）细胞在成功妊娠中发挥着重要作用；然而，γδΤ细胞在蜕膜中的居留和极化仍不清楚。在这项研究中，我们观察到正常妊娠蜕膜中基质细胞（DSCs）上的核因子-κ B 配体（RANKL）受体激活物（RANKL）及其受体 RANK 的水平高于复发性自然流产（RSA）患者。DSCs 表达的 RANKL 可以诱导外周血 γδΤ（pγδΤ）和 dγδΤ 细胞向 Foxp3+γδΤ 细胞极化，并上调转化生长因子（TGF）-β1 的表达。这个过程是通过激活核因子 kappa 轻链增强子的 B 细胞（NF-κB）来介导的。此外，RANKL 促进 dγδΤ 细胞在体外与 DSCs 的黏附，这与 DSCs 上 ICAM-1 和 VCAM-1 的上调以及 dγδΤ 细胞上整合素的上调有关。RANKL 敲除导致小鼠子宫总 γδΤ 细胞、Foxp3+γδΤ 细胞数量减少和 TGF-β1 的表达减少，以及妊娠丢失增加。这些结果表明，RANKL 通过触发 TGF-β1 产生的 Foxp3+γδΤ 细胞在早孕时的极化和居留，是母胎耐受的关键调节因子。由于 DSCs 和 dγδΤ 细胞之间的对话紊乱，RANKL/RANK 的异常低水平导致妊娠丢失。这一观察为检测潜在的标记物以早期预警妊娠丢失提供了科学依据。
