CXCR4+蜕膜NK细胞在人早孕期母-胎界面的表型及其调节作用

The establishment of a successful pregnancy has been proven to be very complicated. From immunological point of view, normal pregnancy can be seen as allograft. The embryo expresses paternal antigens foreign to the mother; therefore, the induction of maternal immune tolerance toward the fetus becomes an important event in the maintenance of early pregnancy. The excessive activation of maternal immune cells against embryo which expresses foreign antigen can result in rejection to the fetus and pregnancy failure. The mechanisms of maternal-fetal immune regulation during pregnancy are still yet to be elucidated. The composition of decidual immune cells is very complicated and special. Decidual NK cells accounts for the majority of decidual immune cells in the early pregnancy. For years, we focused on the biological events related to NK cells at maternal-fetal interface. Our previous studies have demonstrated the role of CXCL12/CXCR4 axis at maternal-fetal interface, and the results have been published. Our recent results suggested that CXCR4 can be used as a subgrouping marker in defining NK cell populations, and CD56brightCXCR4+NK cells are preferentially accumulated at maternal fetal interface of first trimester women. Thus, here we are about to study different subgroups of NK cells in successful and unsuccessful pregnancies, and examine the distribution and cytokine secretion profiles of different subsets of NK cells. We speculate that CD56brightCXCR4+NK cells possess a unique ability to prevent local inflammation and to maintain immune tolerance by inducing Th2 bias and serve a key role in Treg conversion in maintaining immune tolerance at the maternal-fetal interface. Trophoblasts play a key part in recruiting and shifting the phenotype of peripheral NK cells toward decidual NK cells via the CXCL12/CXCR4 axis. And this research might be helpful in improving pregnant outcome, and be of great interest for researchers of reproductive medicine.

正常妊娠需要母体对胎儿自然移植物的免疫耐受。反复自然流产等母-胎免疫调节紊乱疾病给家庭和社会造成巨大损失，然而母-胎免疫耐受的确切机制尚不明确。申请人关注在母-胎界面优势存在的NK细胞的表型和功能，解析NK细胞在母-胎对话和母-胎免疫调节中的作用，相关成果已发表SCI论文。我们的前期研究发现，滋养细胞可通过CXCL12/CXCR4轴诱导母-胎界面Th2型免疫优势。我们最近的研究还表明，CXCR4可作为NK细胞良好的分群标志，且正常妊娠时蜕膜CXCR4+NK细胞在母-胎界面显著富集。本项目将首次基于CXCR4对NK细胞进行分群；解析人早孕滋养细胞对各群NK细胞表型及功能的调节作用及其机制并探讨母-胎界面NK细胞的来源；解析蜕膜CXCR4+NK细胞在母-胎界面免疫优势形成及母-胎免疫耐受建立中的作用及其机制。旨在提出母-胎免疫耐受机理的一些新见解，以期为相关临床疾病的防治提供新的理论依据。

妊娠是一个复杂的生理过程。从免疫学角度来看，正常妊娠中母体对携带父系抗原的胚胎不仅不排斥，而且通过精细的母-胎对话建立起独特的母-胎界面免疫耐受微环境，允许胎儿在母体子宫内生长直到分娩。母-胎界面主要包括滋养细胞、蜕膜基质细胞、蜕膜腺上皮细胞以及免疫细胞。其中50-70% 的蜕膜免疫细胞为蜕膜NK 细胞。趋化因子通过配受体相互作用，构成了人体内复杂的趋化因子网络，执行着复杂的生物学功能。本研究从NK细胞的角度研究母-胎界面发生的生物学事件，阐述母-胎免疫调节的机制，（1）首次基于CXCR4的表达对NK细胞进行分群，解析不同分群NK细胞之间的表型及功能差异；（2）探讨母-胎界面蜕膜NK细胞的来源；（3）解析人早孕滋养细胞对NK细胞表型及功能的调节作用及其机制；（4）解析蜕膜CXCR4+NK细胞在母-胎界面Th2型免疫优势和母-胎耐受建立过程中的作用及其机制。我们的研究发现：（1）基于CXCR4及CD56的表达可以对人早孕期外周及局部NK细胞进行分群，早孕期母-胎界面蜕膜局部CXCR4+ NK 细胞呈现耐受表型及 Th2 型优势，并在正常早孕妇女蜕膜组织中显著富集；（2）滋养细胞通过分泌CXCL12对外周NK细胞产生趋化作用，有利于 NK细胞在母-胎界面富集及发挥作用；（3）母-胎界面滋养细胞能够诱导外周NK细胞的表型和功能向蜕膜NK细胞发生偏移，滋养细胞可使外周CXCR4+ NK细胞朝向蜕膜CXCR4+及CXCR4- NK 细胞分化；（4）蜕膜CXCR4+ NK细胞能够诱导naïve CD4+ T细胞向Th2型细胞分化，诱导CD4+CD25- T细胞向CD4+Foxp3+ Treg细胞转化，促进母-胎界面Th2型免疫优势和免疫耐受。这些结果提示NK细胞，特别是蜕膜CXCR4+NK细胞，在正常妊娠的建立和维持中发挥重要作用。本研究对于人类自然流产等妊娠疾患的防治具有重要意义。由于母-胎免疫耐受是自然界免疫逃逸良好的生理性模型，本研究对移植免疫学和肿瘤免疫学研究亦将产生积极推动作用。