Natural Killer Cells in Pregnancy

怀孕期间的自然杀伤细胞

• 批准号: 7964789
• 负责人: Eric O Long
• 金额: $ 22.04万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7964789
• 关键词: Affinity Chromatography; Arteries; Binding; Biological; Blood flow; CD158d; Cell Communication; Cells; DNA Repair; DNA-PKcs; Development; Endosomes; Environment; Fetus; Genes; HLA G antigen; Histocompatibility; Human; Invaded; Leukocytes; Link; Lymphocyte; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Molecular; NF-kappa B; Natural Killer Cells; Nutrient; Phosphorylation; Pregnancy; Process; Production; Property; Protein-Serine-Threonine Kinases; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; T-Lymphocyte; Tissues; Uterus; Vascular blood supply; Vascular remodeling; Work; chemokine; cytokine; cytotoxicity; fetal; fetus cell; implantation; receptor; response; trophoblast

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.

人类早期妊娠期间的植入部位的特征是脉管系统的大量重塑，胎儿滋养细胞细胞的侵袭以及大量的母体NK细胞。在怀孕的前十二周发生的孕产妇脉管系统的重塑对于为胎儿建立足够的血液供应至关重要。 NKTROPHAST细胞相互作用如何影响血管重塑是未知的。来自胎儿的入侵滋养细胞表达了非古典主要组织相容性I类HLA-G。长期以来，HLA-G的作用是抑制母体NK细胞，否则会攻击胎儿。但是，我们的工作导致对NK细胞在怀孕中的功能的完全不同。我们已经确定KIR2DL4（也称为CD158D）是HLA-G的受体。 KIR2DL4结合可溶性HLA-G分子并将其内部内部化为NK细胞内部内体室。 KIR2DL4具有几乎完全居住在内体中的独特属性。内体正在作为专门的信号室出现，这些信号室具有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尚不清楚。与其他介导NK细胞细胞毒性抑制的KIR不同，KIR2DL4触发了有限的细胞因子和趋化因子的产生。 KIR2DL4激活的基因谱具有典型的促炎和促血管生成特征。 这些发现提出的两个主要问题是将KIR2DL4转运到内体的机制，一旦肯定在内体内可溶于HLA-G，kiR2DL4触发的信号传导途径。通过使用串联亲和力纯化和质谱法，我们已经确定了与KIR2DL4相关的新信号分子，并阐明了将KIR2DL4与激活特定基因的激活联系起来的信号传导途径。 KIR2DL4与丝氨酸/苏氨酸激酶DNA-PKC结合，在DNA修复中具有重要作用。但是，在KIR2DL4信号传导的背景下，DNA-PKC促进了AKT募集到内体，并诱导DNA-PKCS依赖性Akt磷酸化。 KIR2DL4在信号传导中对DNA-PKC，AKT和NF-kappab的顺序需求描述了一种新的内体信号传导途径，以释放一组独特的促炎和促启发性介体，以响应可溶性HLA-G。