Galectin9/Tim3相互作用调节蜕膜CD4+T细胞分化与功能的分子机制

The success of pregnancy depends on the tolerance of maternal immune system to embryonic antigens. The disregulation of maternal-fetal immune would result in pregnancy loss. We have reported that decidual Th2 bias and regulatory T cell expansion are crucial for successful pregnancy.The family of T cell immunoglobulin mucin (Tim) plays important roles in T cell tolerance. Our preliminary data show Tim-3 and its ligand galectin 9 are decreased in embryo trophoblasts and decidual stromal cells from unexplained miscarriage compared with that from normal pregnancy. The expression of Tim 3 in CD4+T subsets (Th1, Th2, Th17 and regulatory T cells) in normal pregnancy are also distinguished with that from unexplained miscarriage. These results suggest that Tim 3 signal is key in the maintenance of CD4+T cell function at the maternal-fetal interface. Our subject will study from the different expression of Tim 3 in human trophoblasts and immune cell subsets at the maternal-fetal interface. We will investigate the regulatory role of galectin 9/Tim 3 in the functional development of decidual CD4+T cells by using cell coculture and CD4+T cell differentiation systems, elucidating the mechanism of materno-fetal tolerance. This work will be helpful in the development of new preventive strategies in materno-fetal disorders such as spontaneous abortion and preeclampsia.

成功妊娠依赖母体对胚胎抗原的免疫耐受，一旦母胎免疫调节异常将导致妊娠失败。我们前期发现，蜕膜局部Th2型优势与调节性T细胞扩增对正常妊娠维持至关重要，其机制仍不明确。T淋巴细胞免疫球蛋白黏蛋白家族分子Tim3在CD4+T细胞功能中发挥重要作用。最近我们发现Tim3及其配体Galectin9在人早孕自然流产滋养细胞表达较正常妊娠显著降低；Tim3在人早孕正常妊娠与自然流产蜕膜、外周血与蜕膜局部CD4+T细胞亚群差异表达，表明Tim3对蜕膜CD4+T细胞亚群表型与功能至关重要。本课题以正常妊娠与自然流产CD4+T细胞亚群差异表达Tim3为切入点，建立细胞共培养与CD4+T细胞分化诱导体系，解析Galectin9/Tim3在早孕蜕膜CD4+T细胞亚群分化与功能中的调节作用，阐明母胎免疫耐受机制，为母胎免疫调节紊乱性疾患的防治提供新策略。

成功妊娠依赖母体对胚胎抗原的免疫耐受，一旦母胎免疫调节异常将会导致妊娠失败。我们前期发现，蜕膜局部Th2型优势对正常妊娠维持至关重要，其机制仍不明确。T淋巴细胞免疫球蛋白黏蛋白家族分子Tim3是最近发现了一个新的免疫抑制性分子，在Th2型优势形成中至关重要，参与机体免疫自稳、感染、肿瘤发生以及慢性移植排斥反应等多种生理与病理过程，然而在母胎耐受中的作用几无报道。本课题以正常妊娠与自然流产母胎界面差异表达Tim3为切入点，通过分离滋养细胞、蜕膜基质细胞与蜕膜免疫细胞亚群，建立细胞共培养体系，并利用正常妊娠与自然流产临床标本与小鼠模型，解析了Galectin9/Tim3在早孕蜕膜基质细胞、CD4T、CD8T细胞与NK细胞功能中的调节作用及其对妊娠结局的影响，主要发现点包括：1）母胎界面与外周血免疫细胞差异表达Tim-3，胚胎滋养细胞有助于维持局部Tim-3 高表达； 2）Tim-3单独或与PD-1优势共表达于蜕膜局部CD4T与CD8T细胞，形成了一群具有增殖与活化能力并具有耐受表型的独特CD4 T细胞与CD8T细胞亚群；干预Tim-3与PD-1信号拮抗这2群细胞产生Th2型细胞因子以及母-胎耐受，增加正常妊娠小鼠模型的胚胎吸收、抑制胚胎生长与发育；3）Tim-3在早孕蜕膜基质细胞的表达能够保护其免遭TLR信号诱导的炎症反应与凋亡并诱导其优势产生Th2型细胞因子；4）滋养细胞分泌Galectin9通过与Tim-3相互作用维持蜕膜NK细胞的耐受表型以及抑制LPS刺激诱导的炎症反应，抑制Tim3/Gal-9信号打破NK细胞的耐受表型，参与自然流产的发生。这些研究结果显示Tim-3/Gal-9信号在早孕母胎免疫耐受与正常妊娠建立与维持中的重要作用与机制，为母胎免疫调节紊乱性疾患的防治提供新策略。