Natural Killer Cells in Pregnancy

人类妊娠早期植入部位的特点是广泛的血管重塑，胎儿滋养层细胞的侵袭，以及母体NK细胞的丰富。孕妇血管系统的重塑发生在怀孕的前12周，对于建立足够的胎儿血液供应是必不可少的。NK-滋养层细胞相互作用如何影响血管重塑尚不清楚。来自胎儿的侵袭性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，人类白细胞抗原-G的作用是抑制母体NK细胞，否则会攻击胎儿。然而，我们的工作导致了对NK细胞在妊娠中的功能的根本不同的理解。 我们已经确定杀伤细胞免疫球蛋白样受体(KIR)2DL4(KIR2DL4，也称为CD158d)是人类白细胞抗原G的受体。KIR2DL4与可溶性的人类白细胞抗原-G结合，并将其内化到NK细胞的胞体内。KIR2DL4具有几乎只存在于内体的独特性质。内小体是最近出现的一种特殊的信号室，赋予受体不同的信号特性。内体信号通路的多样性及其在各种生物反应中的作用尚不清楚。KIR2DL4是一种驻留在NK细胞上的内小体受体，它能刺激一系列独特的促炎和促血管生成介质的释放，以回应可溶性的人类白细胞抗原-G。 这些发现提出的两个主要问题是KIR2DL4向内体转运的机制，以及KIR2DL4一旦与内体中可溶性的人类白细胞抗原-G结合后触发的信号通路。我们已经确定了KIR2DL4信号级联。KIR2DL4对可溶性激动剂抗体或可溶性HLA-G的反应依赖于核因子kB(NF-kB)和丝氨酸苏氨酸激酶Akt的激活。KIR2DL4与DNA依赖蛋白激酶催化亚单位(DNA-PKcs)结合，促进Akt向内体募集，并刺激DNA-PKcs依赖的Akt磷酸化。KIR2DL4对DNA-PKcs、Akt和NF-kB在信号传递中的顺序要求描绘了一条先前未知的NK细胞促炎反应的内体信号通路。 我们进一步确定了KIR2DL4介导的促炎/促血管生成反应启动和维持的分子机制。这种由可溶性配体诱导的内体信号通路将NK细胞驱动到衰老状态，在这种状态下，它们既不会增殖，也不会发生凋亡。相反，它们是代谢活性和分泌介质，促进血管生成和组织重塑。这对人类白细胞抗原G表达部位的NK细胞功能有一定的影响，如妊娠早期植入部位的血管重塑和表达人类白细胞抗原G的肿瘤细胞部位。

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 NK-trophoblast 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 the killer cell immunoglobulin-like receptor (KIR) 2DL4 (KIR2DL4, also known as CD158d) as the receptor for HLA-G. KIR2DL4 binds soluble HLA-G and internalizes it into endosomal compartments inside NK cells. KIR2DL4 has the unique property of residing almost exclusively in endosomes. Endosomes have emerged recently as specialized signaling compartments that endow receptors with distinct signaling properties. The diversity of endosomal signaling pathways and their contribution to various biological responses are still unclear. KIR2DL4 is an endosome-resident receptor in NK cells that stimulates the release of a unique set of proinflammatory and proangiogenic mediators in response to soluble HLA-G. Two major questions raised by these findings are the mechanisms for transport of KIR2DL4 to endosomes, and the signaling pathway triggered by KIR2DL4 once it is bound to soluble HLA-G within endosomes. We have identified the KIR2DL4 signaling cascade. In response to soluble agonist antibody or soluble HLA-G, signaling by KIR2DL4 was dependent on the activation of nuclear factor kB (NF-kB) and the serine-threonine kinase Akt. KIR2DL4 associated with the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), promoted the recruitment of Akt to endosomes, and stimulated the DNA-PKcs dependent phosphorylation of Akt. The sequential requirement for DNA-PKcs, Akt, and NF-kB in signaling by KIR2DL4 delineates a previously uncharacterized endosomal signaling pathway for a proinflammatory response in NK cells. We have further identified the molecular mechanism by which the KIR2DL4-mediated proinflammatory/proangiogenic response is initiated and sustained. This endosomal signaling pathway induced by soluble ligand drives NK cells to a senescent state where they neither proliferate nor undergo apoptosis. Instead, they are metabolically active and secrete mediators that promote angiogenesis and tissue remodeling. This has implications for NK cell function at sites of HLA-G expression such as vascular remodeling at the implantation site during early pregnancy and at the site of HLA-G expressing tumor cells.