雌激素通过下调母-胎界面IL-24表达调节蜕膜NK细胞分化发育的分子机制

The decidual NK cells account for 50%-70% in all decidual immune cells, have a unique phenotype and play an important role in regulating maternal-fetal immunotolerance.Our previous study has demonstrated that estrogen down-regulated the expression of IL-24 and further promoted the growth of decidual stromal cells (DSC) by estrogen receptor ERβ.Compared with normal pregnacy, the decidua from patients with spontaneous abortion have high level of IL-24 and low level of ERβ. Relative to CD56bright NK cells, the CD56dimNK cells of peripheral blood and decidua expressed high IL-24 receptor.Therefore, we speculate that the low lever of ERβ in decidua may lead to the abnormal high expression of IL-24, further inducing the abnormal differentiation of decidual NK and the origin of spontaneous abortion.Thus, the study subjects of this project are NK cells of peripheral blood and decidua.After co-culture with DSCs pretreated with estrogen, we investigate the phenotype and functional changes of NK cells, and further explore the regulatory mechanism of estrogen and IL-24 on the differentiation from peripheral blood NK cells to decidual NK cells.Our project will focus on the develpmental regulation of decidual NK cells from prgnancy women, and explore the regulatory mechanism of estrogen on the formation and maintenance of maternal-fetal immune tolerance. The present research may provide new scientific evidence for maternal-fetal immuno-disorder desease's prevention and treatment.

NK细胞占蜕膜免疫细胞50-70%，具有独特表型，在母-胎耐受中发挥重要作用。我们前期工作证实滋养细胞可趋化外周NK细胞到达蜕膜局部。我们新近发现雌激素通过ERβ下调蜕膜基质细胞（DSC）IL-24进而促进DSC生长。自然流产患者蜕膜高表达IL-24，低表达ERβ。相对于CD56brightNK细胞，外周血和蜕膜CD56dimNK细胞高表达IL-24受体。因此推测蜕膜ERβ低表达可能介导IL-24异常高表达，导致dNK细胞分化发育异常，促进自然流产发生。故本课题以外周血与dNK为研究对象，通过与经雌激素预处理的DSC共培养，研究NK细胞表型与功能变化；进一步解析雌激素和IL-24在外周NK细胞向dNK细胞功能性发育过程中的调节作用及其信号通路。本研究从妊娠期dNK细胞功能性发育调控入手，解析雌激素在母-胎免疫耐受形成和维持中的调节作用机制，为母-胎免疫调节紊乱性疾病的防治提供新的科学依据。

NK细胞占蜕膜免疫细胞50-70%，具有独特表型，在母-胎耐受中发挥重要作用。NK细胞的功能性发育过程是通过其表面活化受体与抑制受体的表达来实现，两者间的平衡是控制NK细胞杀伤活性的重要机制。我们研究发现子宫内膜蜕膜化进程中IL-24表达显著升高。相对于外周NK细胞，蜕膜NK细胞高表达IL-24受体（IL-20R1和IL-22R1）；CD56dim NK细胞表面IL-24受体表达水平显著高于CD56bright NK细胞。蜕膜基质细胞分泌的IL-24可抑制外周和/或蜕膜NK细胞CD16、颗粒酶B、穿孔素和 γ干扰素的表达，相反，上调TGF-β、IL-10和IL-8的表达，从而利于在早孕期母-胎界面诱导蜕膜NK细胞呈CD16-GranzymeB-peforin- KIR2DL1+KIR3DL1+TGF-β+IL-10+IL-8+优势表型。这群NK具有较低细胞毒活性、高免疫调节和促血管生成的生物学功能，在正常妊娠建立和维持中发挥重要调节作用。这些研究诠释了IL-24通过加强蜕膜基质细胞与蜕膜NK细胞交互并促进母-胎免疫耐受的分子机制，对于完善母-胎交互对话理论和母-胎免疫耐受机制具有重要科学价值。