滋养细胞通过IL-35调控Treg/Th17细胞平衡促进妊娠维持的机制研究

Embryonic-derived trophoblasts and maternal-derived decidual immune cells play an important role in maternal fetal immune tolerance. Previous studies in our research group found that serum levels of IL-35 increased in normal pregnancy, return to normal in postpartum, and decreased in recurrent spontaneous abortion. IL-35 was expressed in syncytiotrophoblast and extrachorionic trophoblast at the maternal-fetal immune tolerance interface, which suggest IL-35 is important in pregnancy maintenance， but its function and mechanism of the immune regulation are not clear. In this study, the relationship between IL-35 expression and Treg/Th17 during pregnancy, and the correlation between imbalance and spontaneous abortion were analyzed in patients with habitual spontaneous abortion. To investigate the differentiation and transformation, quantity and function of ovarian tissue immune cells (native T, Teff, Treg, Th17 cells) by trophoblast-derived IL-35 via receptor (IL-12Rβ2, gpl30) and JAK-STAT signaling pathways.IL-35 promotes the dynamic balance of Treg and Th17 cells, thereby promoting the mechanism of pregnancy maintenance. In the mouse model of spontaneous abortion, the ability of recombinant IL-35 to induce maternal and fetal immune tolerance was analyzed, and the effect of IL-35 on pregnancy outcome was determined. The purpose of this study was to enrich the theory of immune tolerance during pregnancy and to provide new ideas for the prevention and treatment of habitual abortion.

胚胎来源的滋养细胞和母体来源的蜕膜免疫细胞在母胎免疫耐受中发挥重要作用。我们前期研究发现外周血IL-35在正常妊娠中升高，产后降至正常，在习惯性流产早孕期降低；妊娠早期合体滋养细胞和绒毛外滋养细胞表达IL-35，提示IL-35在母胎免疫耐受维持中至关重要，但其功能与作用机制不清。本课题将以习惯性流产患者为对象，分析IL-35表达与Treg/Th17的关系，及其失衡与自然流产的相关性。探讨滋养细胞来源的IL-35通过受体（IL-12Rβ2、gpl30）和JAK-STAT信号通路调控蜕膜免疫细胞（native T、Teff、Treg、Th17细胞）的分化与转化、数量与功能，促使Treg和Th17细胞形成动态平衡，促进妊娠维持的机制。在自然流产小鼠模型中，分析重组IL-35诱导母胎免疫耐受建立的能力，明确IL-35对妊娠结局的影响。本研究旨在丰富孕期免疫耐受理论并为习惯性流产的防治提供新思路。

胚胎来源的滋养细胞和母体来源的蜕膜免疫细胞在母胎免疫耐受中发挥重要作用。我们研究发现外周血IL-35在正常妊娠中升高，产后降至正常，在习惯性流产早孕期降低；妊娠早期合体滋养细胞和绒毛外滋养细胞表达IL-35，提示IL-35在母胎免疫耐受维持中至关重要。与对照组相比，习惯性自然流产患者胎盘IL-35表达下调，葡萄胎患者胎盘IL-35表达上调。滋养细胞与nativeT细胞共培养，可以上调foxp3表达，下调IL-17表达。IL-35可以抑制效应T细胞增殖，诱导效应性T细胞表达IL-35。STAT3和STAT4是IL-35主要下游信号通路。本研究丰富了孕期免疫耐受理论并为习惯性流产的防治提供新思路，未来IL-35有望成为习惯性自然流产的筛查指标。