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。 内体先天受体CD158d（KIR2DL4）响应于可溶性配体（HLA-G或激动剂抗体）诱导人NK细胞中的细胞衰老。这些衰老NK细胞显示衰老相关分泌表型（SASP），并且它们的分泌组促进血管重塑和血管生成。为了了解CD158d如何启动衰老反应的信号传导，我们绘制了其胞质尾区中控制信号传导的区域。我们鉴定了一个保守的TRAF6结合基序，这是CD158 d诱导的NF-B活化和IL-8分泌、TRAF6与CD158 d结合以及TRAF6募集到转染细胞中的CD158 d+内体所必需的。κ已知衔接子TRAF6通过激酶TAK1偶联来自受体如内体TLR和CD40的近端信号，用于NF-B依赖性促炎反应。κ siRNA介导的TRAF6和TAK1的沉默以及TAK1的抑制阻断了CD158 d依赖性IL-8的分泌。用针对CD158d的可溶性Ab刺激原代静息NK细胞诱导TAK1磷酸化，并且TAK1的抑制阻断产生SASP特征的NK细胞的CD158d依赖性重编程。我们的研究结果表明，一个原型TLR和TNF受体信号通路被一个杀伤细胞免疫球蛋白样受体所使用，该受体促进促炎和促血管生成介质的分泌，作为NK细胞独特衰老表型的一部分

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. The endosomal innate receptor CD158d (KIR2DL4) induces cellular senescence in human NK cells in response to soluble ligand (HLA-G or agonist antibody). These senescent NK cells display a senescence-associated secretory phenotype (SASP) and their secretome promotes vascular remodeling and angiogenesis. To understand how CD158d initiates signaling for a senescence response, we mapped the region in its cytoplasmic tail that controls signaling. We identified a conserved TRAF6 binding motif, which was required for CD158d-induced NF-κB activation and IL-8 secretion, for TRAF6 association with CD158d, and for TRAF6 recruitment to CD158d+ endosomes in transfected cells. The adaptor TRAF6 is known to couple proximal signals from receptors such as endosomal TLRs and CD40 through the kinase TAK1 for NF-κB-dependent pro-inflammatory responses. siRNA-mediated silencing of TRAF6 and TAK1, and inhibition of TAK1 blocked CD158d-dependent IL-8 secretion. Stimulation of primary, resting NK cells with soluble Ab to CD158d induced TAK1 phosphorylation, and inhibition of TAK1 blocked the CD158d-dependent reprogramming of NK cells that produces the SASP signature. Our results reveal that a prototypic TLR and TNF-receptor signaling pathway is used by a killer cell immunoglobulin-like receptor that promotes secretion of pro-inflammatory and pro-angiogenic mediators as part of a unique senescence phenotype in NK cells