Functional analysis of a novel inhibitory receptor expressed on plasmacytoid dendritic cells

抑制性受体通过负性调节细胞功能，在精细调节和终止免疫应答中发挥关键作用。已经在各种类型的细胞上鉴定了许多抑制性受体。特别是，自然杀伤细胞上的抑制性受体已经得到很好的表征。据推测，通过抑制性NK受体识别靶细胞上的MHC I类或相关分子，允许NK细胞防止自我杀伤，但破坏具有降低水平的MHC I类的不适当的细胞。Ly 49 Q是一种携带ITIM的抑制性受体，属于Ly 49家族，该家族被称为NK受体的亚家族之一。尽管Ly 49 Q由于其高度的结构相似性和染色体位置而被归类为Ly 49家族，但Ly 49 Q具有不同于其他Ly 49家族成员的独特特征。Ly 49 Q在NK和NKT细胞上不表达，但主要在巨噬细胞和浆细胞树突状细胞上表达。ly 49 q有一个abi ...更多信息 在本研究中，我们使用导入野生型（WT）或ITIM缺失突变型（YF）cDNA的小鼠，在体外和体内研究Ly 49 Q在中性粒细胞粘附和迁移中的作用。在没有炎症刺激的情况下，Ly 49 Q-WT而不是Ly 49 Q-YF通过防止粘着斑形成来抑制牢固的粘着和扩散，表明Ly 49 Q防止稳态条件下的危险粘着。在炎症情况下，Ly 49 Q-YF的表达，这是ITIM依赖性信号的无能，导致减少组织浸润的中性粒细胞在早期阶段。这是由于响应于fMLP的细胞极性组织的缺陷。相反，Ly 49 Q-WT通过增强Ly 49 Q的表达而引起中性粒细胞浸润的增强。此外，Ly 49 Q-WT而非Ly 49 Q-YF小鼠在外周淋巴器官中自发发生出血，伴有中性粒细胞增加。Ly 49 Q的这些功能似乎是通过改变自身的细胞内定位，以化学引诱物刺激和ITIM依赖的方式调节相关SHP-1的细胞内定位来介导的。因此，中性粒细胞上的Ly 49 Q是一种关键分子，不仅调节稳态下的稳态调节，而且调节炎症后的紧急迁移。少

Inhibitory receptors play crucial roles for fine regulation and termination of immune responses by negatively regulating cellular functions. A number of inhibitory receptors have been identified on various types of cells. In particular, inhibitory receptors on natural killer cells have been well characterized. It has been postulated that recognition of MHC class I, or related molecules, on target cells by inhibitory NK receptors allows NK cells to prevent self killing but destroy inappropriate cells possessing decreased levels of MHC class I.Ly49Q is an ITIM-bearing inhibitory receptor belonging to Ly49 family that is known as one of subfamilies of NK receptors. Even though Ly49Q is classified into Ly49 family because of highly structural similarities and of its chromosomal location, Ly49Q has unique features different from other Ly49 family members. Ly49Q is not expressed on NK and NKT cells, but predominantly expressed on macrophages and plasmacytodi dendritic cells. Ly49Q has an abi … More lity to associate with both SHP-1 and SHP-2 in a tyrosine phosphorylation-dependent manner.In this study, we explored role of Ly49Q in adhesion and migration of neutrophils using mice introducing with wild type (WT) or the ITIM-less mutant (YF) cDNA in both in vitro and in vivo. In the absence of inflammatory stimuli, Ly49Q-WT but not Ly49Q-YF inhibited firm adhesion and spreading by preventing of focal adhesion formation, suggesting that Ly49Q prevents hazardous adhesion in steady-state condition. In inflammatory situation, expression of Ly49Q-YF, which is incompetent for the ITIM-dependent signal, caused reduced tissue infiltration of neutrophils at an early stage. This was due to defects in organization of cellular polarity in response to fMLP. Contrary, Ly49Q-WT gave rise to the augmentation of neutrophil infiltration by the enhanced expression of Ly49Q. Furthermore, Ly49Q-WT, but not Ly49Q-YF mice, spontaneously developed hemorrhage in peripheral lymphoid organs accompanied with the increase in neutrophils. These functions of Ly49Q appeared to be mediated by regulating intracellular localization of associated SHP-1 in the chemoattractant stimuli-and the ITIM-dependent manner by changing own intracellular localization. Thus, Ly49Q on neutrophils is a pivotal molecule to regulate not only homeostatic regulation in steady state but also urgent migration upon inflammation. Less