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。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。 我们已经鉴定了杀伤细胞免疫球蛋白样受体（KIR）2DL 4（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。内体最近出现了专门的信号室，赋予受体不同的信号特性。内体信号通路的多样性及其对各种生物学反应的贡献仍不清楚。KIR 2DL 4是NK细胞中的内体驻留受体，其响应于可溶性HLA-G刺激一组独特的促炎和促血管生成介质的释放。 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结合就触发的信号通路。我们已经鉴定了KIR 2DL 4信号级联。响应于可溶性激动剂抗体或可溶性HLA-G，通过KIR 2DL 4的信号传导依赖于核因子kB（NF-kB）和丝氨酸-苏氨酸激酶Akt的活化。KIR 2DL 4与DNA依赖性蛋白激酶催化亚基（DNA-PKcs）结合，促进Akt向核内体的募集，刺激Akt的DNA-PKcs依赖性磷酸化。在KIR 2DL 4信号传导中对DNA-PKcs、Akt和NF-kB的顺序要求描绘了NK细胞中促炎反应的先前未表征的内体信号传导途径。 我们进一步确定了KIR 2DL 4介导的促炎/促血管生成反应启动和持续的分子机制。这种由可溶性配体诱导的内体信号传导途径驱动NK细胞进入衰老状态，其中它们既不增殖也不经历凋亡。相反，它们具有代谢活性并分泌促进血管生成和组织重塑的介质。这暗示了NK细胞在HLA-G表达位点的功能，例如在早期妊娠期间植入位点和在HLA-G表达肿瘤细胞位点的血管重塑。

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.