Regulation Of Natural Killer Cell Activity

自然杀伤（NK）细胞是除B和T细胞之外的第三种淋巴细胞亚型。NK细胞在防御病毒和其他细胞内病原体方面提供重要的免疫功能。与B和T细胞不同，NK细胞不表现出对抗原的特异性。它们之所以得名，是因为它们可以在没有抗原刺激的情况下杀死细胞。NK细胞上识别主要组织相容性I类分子的抑制性受体阻止了对正常健康细胞的杀伤。已经描述了大量调节NK细胞的细胞毒性应答的活化和抑制受体。为了评价单个受体对控制NK细胞活化的贡献，使用了给定NK细胞抑制性受体缺陷的小鼠。此外，还对与人NK细胞上杀伤细胞免疫球蛋白样受体（KIR）等同的小鼠受体进行了研究。 小鼠抑制性受体gp49B是有趣的，因为它在几种细胞类型上表达，这些细胞类型可以在激活过程中释放颗粒。这样的细胞包括NK细胞、肥大细胞和嗜中性粒细胞。嗜酸性粒细胞流入气道空间是过敏性哮喘的特征，并可能导致发病机制，如气道高反应性和重塑，以及过度的粘液产生。我们已经表明，嗜酸性粒细胞在过敏性炎症过程中对小鼠肺部的浸润受抑制性受体gp49B的阴性控制。gp49 B是一种Ig样受体，已知其通过其胞质尾区的基于免疫受体酪氨酸的抑制基序（ITIM）负调节肥大细胞和中性粒细胞。使用gp49B缺陷的小鼠（gp49B KO），我们观察到与C57 BL/6野生型对照相比，猪蛔虫感染的豚草（RW）致敏小鼠在RW攻击后肺中的过敏性炎症增加。在对照小鼠外周血嗜酸性粒细胞和RW致敏和激发的动物肺嗜酸性粒细胞上检测到gp49B的表达。此外，与C57 BL/6对照组相比，在眼内激发的RW致敏gp49 B KO动物中观察到结膜炎症增加，以嗜酸性粒细胞、中性粒细胞和脱颗粒肥大细胞为主。这些数据提供了嗜酸性粒细胞上功能性抑制受体的证据，其具有抑制嗜酸性粒细胞介导的过敏性炎症的重要保护功能。 免疫系统和神经系统的一个共同特性是通过高度复杂和适应性强的细胞相互作用网络进行调节。主要组织相容性复合物（MHC）I类分子是CD8 T细胞上的抗原特异性受体和NK细胞上的抑制性受体的配体，在中枢神经系统（CNS）中的活性依赖性神经元可塑性的控制中具有重要且令人惊讶的作用。虽然已经报道了MHC I类分子在神经元中的表达，但在中枢神经系统中还没有鉴定出相应的免疫受体。我们已经表明，杀伤细胞免疫球蛋白样受体（KIR）基因选择性地表达在小鼠大脑的突触可塑性和神经发生的亚区，包括嗅球，吻侧迁移流，海马齿状回。这些结果提示KIR在CNS中的新功能。 人类妊娠早期子宫组织的特征是广泛的血管重塑、胎儿滋养层细胞的侵袭和大量的母体自然杀伤（NK）细胞。滋养层细胞表达非经典主要组织相容性I类分子HLA-G的膜结合和可溶性同种型。NK-滋养层细胞相互作用如何影响血管重塑尚不清楚。我们已经证明，静息NK细胞分泌干扰素γ是由可溶性的，但不是固相抗体诱导的杀伤细胞免疫球蛋白样受体（KIR）2DL4，HLA-G的受体。KIR2DL4通过动力蛋白依赖性过程组成性内化到Rab5阳性隔室中。如共聚焦显微镜所示，可溶性HLA-G被内吞到NK细胞和用KIR2DL4转染的293T细胞中含有KIR2DL4的隔室中。通过静息NK细胞上的KIR2DL4接合上调的基因谱表明在血管形成中的作用。IL-8分泌通过将KIR2DL4转染到293T细胞中来诱导，并且仅在运输到内体的重组形式的KIR2DL4的情况下发生。我们提出胎儿滋养层细胞产生的可溶性HLA-G通过KIR2DL4的内吞作用激活母体NK细胞，从而促进植入过程中的血管形成。

Natural killer (NK) cells are a third subtype of lymphocytes besides B and T cells. NK cells provide an important immune function in the defense against viruses and other intracellular pathogens. Unlike B and T cells, NK cells do not exhibit specificity for antigen. They acquired their name because they can kill cells without prior stimulation by antigen. The killing of normal healthy cells is prevented by inhibitory receptors on NK cells that recognize major histocompatibility class I molecules. A large number of receptors, both activating and inhibitory, that regulate the cytotoxic response of NK cells have been described. In order to evaluate the contribution of individual receptors to the control of NK cell activation, mice defective in a given NK cell inhibitory receptor have been used. In addition, a search for the mouse receptor equivalent to the killer cell immunoglobulin-like receptors (KIR) on human NK cells was undertaken. The mouse inhibitory receptor gp49B is interesting because it is expressed on several cell types that can release granules during activation. Such cells include NK cells, mast cells, and neutrophils. An influx of eosinophils into airway spaces is characteristic of allergic asthma and may contribute to pathogenesis such as airway hyperresponsiveness and remodeling, as well as excessive mucus production. We have shown that infiltration of mouse lungs by eosinophils during allergic inflammation is under negative control by the inhibitory receptor gp49B. gp49B, an Ig-like receptor, is known to negatively regulate mast cells and neutrophils through immuno-receptor tyrosine-based inhibition motifs (ITIM) in its cytoplasmic tail. Using mice deficient in gp49B (gp49B KO), we observed an increase in allergic inflammation in the lungs of Ascaris suum-infected, ragweed (RW) sensitized mice upon RW challenge, as compared to C57BL/6 wild type controls. Expression of gp49B was detected on peripheral eosinophils of control mice and on eosinophils from lungs of animals sensitized and challenged with RW. Furthermore, an increase in conjunctival inflammation, with a predominance of eosinophils, neutrophils, and degranulated mast cells, was observed in RW-sensitized gp49B KO animals that had been challenged in the eye, as compared to C57BL/6 controls. These data provide evidence of a functional inhibitory receptor on eosinophils which has the important protective function of dampening eosinophil-mediated allergic inflammation. A property common to the immune system and the nervous system is regulation by a highly complex and adaptable network of cellular interactions. Major histocompatibility complex (MHC) class I molecules, which are ligands of antigen-specific receptors on CD8 T cells and of inhibitory receptors on NK cells, have an important and surprising role in the control of activity-dependent neuronal plasticity in the central nervous system (CNS). While expression of MHC class I molecules in neurons has been reported, corresponding immune receptors have not been identified in the central nervous system. We have shown that a killer cell imunoglobulin-like receptor (KIR) gene is selectively expressed in subregions of the mouse brain where synaptic plasticity and neurogenesis occur, including olfactory bulbs, rostral migratory stream, and dentate gyrus of hippocampus. These results suggest new functions for KIR in the CNS. Uterine tissue in early human pregnancy is characterized by extensive vascular remodeling, invasion of fetal trophoblast cells, and by an abundance of maternal natural killer (NK) cells. Trophoblast cells express membrane-bound and soluble isoforms of the non-classical major histocompatibility class I molecule HLA-G. How NK-trophoblast cell interactions influence vascular remodeling is unknown. We have shown that interferon-gamma secretion by resting NK cells is induced by soluble, but not solid-phase antibodies to the killer cell immunoglobulin-like receptor (KIR) 2DL4, a receptor for HLA-G. KIR2DL4 is constitutively internalized into Rab5-positive compartments by a dynamin-dependent process. Soluble HLA-G was endocytosed into KIR2DL4-containing compartments in NK cells and in 293T cells transfected with KIR2DL4, as shown by confocal microscopy. The profile of genes upregulated by KIR2DL4 engagement on resting NK cells suggests a role in vascularization. IL-8 secretion was induced by transfection of KIR2DL4 into 293T cells, and occurred only with recombinant forms of KIR2DL4 that trafficked to endosomes. We propose that soluble HLA-G produced by fetal trophoblast cells activates maternal NK cells through endocytosis of KIR2DL4, thereby promoting vascularization during implantation.