CXCL16/CXCR6介导滋养细胞与γδT细胞相互作用的分子机制

In recent studies, we found that expression of CXCL16/CXCR6 at the maternal-fetal interface on RSA is obviously lower than that of normal pregnancy women. That illustrates misexpression of CXCL16/CXCR6 is associated with pathologic pregnancy in early pregnancy. However, it should be further elucidated that the regulatory mechanism of CXCX16/CXCR6 on normal pregnancy and recurrent spontaneous abortion. Therefore, the project will focus on CXCL16/CXCR6, and probe into whether trophoblasts regulate biological function of decidual gamma-delta T cells via CXCL16/CXCR6. Moreover, if the signal pathways that trophbalsts influent gamma-delta T cells via CXCL16/CXCR6 are through PI3K/AKT and/or MAPK pathways. Furtherly, the role of CXCL16 in gamma-delta T cells reguluating functions of trphoblasts will also be illustrated. The study will furtherly illucidate mechanism of the cross-talk between trophoblasts and gamma-delta T cells at the maternal-fetal interface. It is not only favor to understand the mechanism of maternal-fetal immune tolerance deeply, which will show a new target for therapeutic action on RSA, but also able to supply scientific basis for prevention and treatment of tophoblasts over-invasion diseases.

我们新近研究发现，反复自然流产患者母-胎界面CXCL16/CXCR6表达明显低于正常妊娠者，提示早孕期母-胎界面CXCL16/CXCR6表达异常可能与病理性妊娠的发生相关。但是，CXCL16/CXCR6这对趋化因子及受体在成功妊娠和反复自然流产中到底发挥怎样的调节机制尚需进一步研究。因此，本项目以CXCL16/CXCR6为切入点，深入研究滋养细胞是否通过CXCL16/CXCR6调节蜕膜γδT细胞的生物学功能；进一步解析滋养细胞来源的CXCL16是否通过其下游PI3K/AKT及MAPK通路发挥调节作用；并揭示CXCL16在γδT细胞调节滋养细胞生物学功能中的作用。本研究有助于我们对母-胎界面滋养细胞与γδT细胞交叉对话机制更深层次的理解，不仅有利于母-胎免疫耐受机制的研究深入，为临床治疗反复自然流产提供新的治疗靶点；而且为拓展滋养细胞侵袭过度性疾病的防治新策略提供科学依据。

γδT细胞在母胎界面发挥着重要的作用，但是我们队γδT细胞与绒毛滋养细胞间的相互作用机制了解的很少。因此，我们就这方面做了相关的研究发现，蜕膜γδT细胞高表达CXCR6，而滋养细胞分泌CXCL16。用孕激素或与滋养细胞系JEG-3细胞共培养能够上调蜕膜γδT细胞的CXCR6的水平。JEG-3细胞分泌的CXCL16促进γδT细胞增殖，并同时降调节蜕膜γδT细胞的IFN-γ、穿孔素及颗粒酶B的水平。CXCL16训导过的蜕膜γδT细胞能够上调Ki-67和Bcl-xL的表达量及降调节Fas和FasL的表达量，从而进一步促进JEG-3细胞的增殖，并降低JEG-3的凋亡。我们研究发现CXCL16/CXCR6在母胎界面蜕膜γδT细胞和滋养细胞交互对话中发挥着重要的作用，抑制蜕膜γδT细胞的杀伤活性和促进滋养细胞的生长，从而维持正常妊娠。