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

抑制受体通过负性调节细胞功能，在精细调控和终止免疫应答中起着至关重要的作用。在不同类型的细胞中已经发现了许多抑制性受体。特别是，自然杀伤细胞上的抑制性受体已被很好地表征。据推测，抑制NK受体在靶细胞上识别MHC I类或相关分子，使NK细胞能够防止自我杀伤，但会破坏MHC I类水平降低的不适当细胞。ly49q是一种含有itim的抑制受体，属于Ly49家族，被称为NK受体亚家族之一。尽管Ly49Q因其高度的结构相似性和染色体位置而被归入Ly49家族，但Ly49Q具有不同于其他Ly49家族成员的独特特征。Ly49Q在NK和NKT细胞上不表达，而主要在巨噬细胞和浆细胞树突状细胞上表达。Ly49Q更倾向于以酪氨酸磷酸化依赖的方式与SHP-1和SHP-2结合。在本研究中，我们利用野生型（WT）或ITIM-less突变型（YF） cDNA引入小鼠，在体外和体内研究了Ly49Q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，Ly49Q- wt而不是Ly49Q- yf通过阻止局灶性粘连的形成来抑制牢固的粘连和扩散，这表明Ly49Q在稳态条件下可以阻止危险的粘连。在炎症情况下，无法表达itim依赖信号的Ly49Q-YF在早期导致中性粒细胞组织浸润减少。这是由于响应fMLP的细胞极性组织缺陷造成的。相反，Ly49Q- wt通过增强Ly49Q的表达使中性粒细胞浸润增加。此外，Ly49Q-WT小鼠，而Ly49Q-YF小鼠，外周血淋巴器官自发出血，并伴有中性粒细胞的增加。Ly49Q的这些功能似乎是通过改变自身的细胞内定位，以趋化刺激和itim依赖的方式调节相关SHP-1的细胞内定位而介导的。因此，中性粒细胞上的Ly49Q不仅是稳定状态下调节稳态调节的关键分子，也是炎症时紧急迁移的关键分子。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