蜕膜组织驻留NK细胞转录调控和发育途径研究

We have demonstrated a special decidual tissue resident NK cells (trNK) which have CD49a+Eomes+ phenotype, are able to secrete a variety of growth factors and promote fetal development. The number and function of trNK cells are closely related to embryonic development. We have also demonstrated that decidual CD27+NK cells can inhibit inflammatory TH17 cells, and maintains the tolerance and immune balance during pregnancy. These special NK subsets in decidua are totally different from the classic NK cells with high cytotoxicity. Thus the phenotype and function of decidual NK subsets are highly heterogeneous. Many new scientific questions appear with the deepening of the research: What are the key transcriptional factors that regulate the CD49a+Eomes+decidual NK subset and other decidual NK subsets? What’s the relationship between the transcriptional factor that regulate the CD49a+Eomes+decidual NK subset and the previously reported transcriptional factor, such as T-bet and Eomes? What are the factors in the microenvironment affecting the expression of transcriptional factor in decidual NK cells, and further affect the development and differentiation of decidual NK cells? The further research of the transcriptional and development regulation of decidual trNK cells at the maternal-fetal interface, can not only rich the oretical connotation of decidual tissue-resident NK cells, but also provide new clinical pathological targets for fetal growth restriction and recurrent spontaneous abortion with unknown reasons.

我们已发现蜕膜组织驻留NK细胞具有CD49a+Eomes+的表型，分泌促胚胎发育的生长因子，其数量及功能与胚胎发育密切相关。我们也发现蜕膜CD27+NK细胞可以有效地抑制炎症TH17细胞，维持母胎耐受。这些蜕膜组织特异性的NK细胞亚群与经典的杀伤功能NK细胞截然不同，展现出显著的异质性。随着研究的深入也出现了很多新的科学问题：调控蜕膜CD49a+Eomes+亚群及其他亚群功能的关键转录因子是什么？这些调控蜕膜NK细胞亚群的转录因子与已报道调控经典NK细胞的转录因子如T-bet,Eomes的关系如何？蜕膜微环境中的哪些因素会影响蜕膜NK细胞转录因子的表达，进而影响蜕膜NK细胞的发育分化？对母胎界面蜕膜组织微环境中NK细胞亚群转录调控和发育途径的深入研究，不仅可以丰富蜕膜组织特异性NK细胞的理论内涵，也为因子宫蜕膜免疫功能失常所导致的胎儿生长受限和不明原因反复流产提供新的临床病理靶标。

前期研究已发现蜕膜组织驻留NK细胞具有CD49a+Eomes+的表型，分泌促胚胎发育的生长因子，其数量及功能与胚胎发育密切相关。我们也发现蜕膜CD27+NK细胞可以有效地抑制炎症TH17细胞，维持母胎耐受。这些蜕膜组织特异性的NK细胞亚群与经典的杀伤功能NK细胞截然不同，展现出显著的异质性。随着研究的深入也出现了很多新的科学问题：调控蜕膜CD49a+Eomes+NK细胞亚群的关键转录因子是什么？该转录因子是如何调控NK细胞促胚胎发育功能的？蜕膜微环境中的哪些因素会影响蜕膜NK细胞转录因子的表达，进而影响蜕膜NK细胞的发育分化？ . 本课题针对母胎界面蜕膜组织特有组织驻留NK细胞（trNK）的表型、功能和转录发育等进行了研究：通过对人子宫trNK细胞全基因表达谱芯片数据分析，揭示PBX1是人子宫trNK细胞中高表达的特异性转录因子，在转录因子PBX1检测过程中制备了抗PBX1的单克隆抗体，目前已获得国家专利。另一方面在人子宫蜕膜组织NK细胞中，揭示了新转录因子PBX1调控生长因子转录表达的分子机制，揭示了妊娠期母胎界面免疫微环境介导胚胎发育的机制和关键效应分子PTN/OGN，发现转录因子PBX1可以直接结合生长因子PTN和OGN的启动子增强其转录表达。上述机制为阐述蜕膜NK细胞促进胚胎早期发育提供新的分子理论基础，不仅可以丰富蜕膜组织特异性NK细胞的理论内涵，也为因子宫蜕膜免疫功能失常所导致的胎儿生长受限和不明原因反复流产提供新的临床病理靶标。