Natural Killer Cells in Pregnancy

人类妊娠早期着床部位的特征是血管系统的广泛重塑、胎儿滋养层细胞的侵入以及大量的母体NK细胞。母体血管系统的重塑发生在妊娠的前12周，对于为胎儿建立足够的血液供应至关重要。滋养层细胞间的相互作用如何影响血管重塑尚不清楚。来自胎儿的侵入滋养层细胞表达非经典的主要组织相容性I类分子HLA-G。长期以来，人们一直认为HLA-G的作用是抑制母体NK细胞，否则这些细胞会攻击胎儿。然而，我们的工作导致了对NK细胞在妊娠中功能的完全不同的理解。我们已经鉴定了KIR 2DL 4（也称为CD 158 d）作为HLA-G的受体。KIR 2DL 4结合可溶性HLA-G分子并将其内化到NK细胞内的内体区室中。KIR 2DL 4具有几乎完全驻留在内体中的独特性质。核内体是一种特殊的信号传导区室，赋予受体不同的信号传导特性。内体信号通路的多样性及其对各种生物学反应的贡献仍不清楚。与介导NK细胞细胞毒性抑制的其他KIR不同，KIR 2DL 4触发有限的一组细胞因子和趋化因子的产生。由KIR 2DL 4激活的基因谱携带典型的促炎症和促血管生成特征。 这些发现提出的两个主要问题是KIR 2DL 4转运到内体的机制，以及KIR 2DL 4一旦与内体内的可溶性HLA-G结合就触发的信号传导途径。通过使用串联亲和纯化和质谱，我们已经确定了一个新的信号分子与KIR 2DL 4和阐明的信号通路，连接KIR 2DL 4与一组特定的基因的激活。KIR 2DL 4与丝氨酸/苏氨酸激酶DNA-PKcs结合，其在DNA修复中具有重要作用。然而，在KIR 2DL 4信号传导的背景下，DNA-PKcs促进Akt募集到内体，并诱导DNA-PKcs依赖性Akt磷酸化。KIR 2DL 4在信号传导中对DNA-PKcs、Akt和NF-kappaB的顺序要求描绘了一种新的内体信号传导途径，用于响应可溶性HLA-G释放一组独特的促炎症和促血管生成介质。

The implantation site during early human pregnancy is characterized by extensive remodeling of the vasculature, invasion of fetal trophoblast cells, and by an abundance of maternal NK cells. The remodeling of the maternal vasculature, which occurs over the first twelve weeks of pregnancy, is essential to establish sufficient blood supply to the fetus. How NKtrophoblast cell interactions influence vascular remodeling is unknown. Invading trophoblast cells from the fetus express the non-classical major histocompatibility class I molecule HLA-G. It was long thought that the role of HLA-G was to inhibit maternal NK cells, which would otherwise attack the fetus. However, our work has led to a radically different understanding of the function of NK cells in pregnancy. We have identified KIR2DL4 (also known as CD158d) as the receptor for HLA-G. KIR2DL4 binds soluble HLA-G molecules and internalizes them into endosomal compartments inside NK cells. KIR2DL4 has the unique property of residing almost exclusively in endosomes. Endosomes are emerging as specialized signaling compartments that endow receptors with distinct signaling properties. The diversity of endosomal signaling pathways and their contribution to various biological responses is still unclear. Unlike other KIRs that mediate inhibition of NK cell cytotoxicity, KIR2DL4 triggers the production of a limited set of cytokines and chemokines. The profile of genes activated by KIR2DL4 carries a typical proinflammatory and proangiogenic signature. Two major questions raised by these findings are the mechanism for transport of KIR2DL4 to endosomes, and the signaling pathway triggered by KIR2DL4 once it is bound to soluble HLA-G within endosomes. By use of tandem affinity purification and mass spectrometry, we have identified a new signaling molecule associated with KIR2DL4 and elucidated the signaling pathway that links KIR2DL4 with the activation of a specific set of genes. KIR2DL4 bound to the serine/threonine kinase DNA-PKcs, which has an important role in DNA repair. However, in the context of KIR2DL4 signaling, DNA-PKcs promoted Akt recruitment to endosomes, and induced DNA-PKcs-dependent Akt phosphorylation. The sequential requirement for DNA-PKcs, Akt, and NF-kappaB in signaling by KIR2DL4 delineates a new endosomal signaling pathway for release of a unique set of proinflammatory and proangiogenic mediators in response to soluble HLA-G.