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

浆细胞样树突状细胞表达的新型抑制性受体的功能分析

基本信息

批准号：
17590445
负责人：
TOYAMA Noriko
金额：
$ 2.3万
依托单位：
International Medical Center of Japan
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590445/
关键词：
inhibitory receptor neutrophils NK receptor MHC class I mouse ケモタキシス炎症フォスファターゼ細胞極性細胞接着インテグリン focal adhesion kinase パキシリン

项目摘要

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

抑制性受体通过负调节细胞功能在免疫反应的精细调节和终止中发挥重要作用，特别是自然杀伤细胞上的抑制性受体已被充分表征。通过抑制性 NK 受体将 MHC I 类或相关分子作用于靶细胞，使 NK 细胞能够防止自我杀伤，但不适当地破坏 MHC I 类水平降低的细胞。Ly49Q 是一种携带 ITIM 的抑制物Ly49Q 属于 Ly49 家族的受体，被称为 NK 受体亚家族之一，尽管 Ly49Q 由于高度结构相似性及其染色体位置而被归类为 Ly49 家族，但 Ly49Q 具有与其他 Ly49 家族成员不同的独特特征。 Ly49Q 在 NK 和 NKT 细胞上表达，但主要在巨噬细胞和浆细胞树突状细胞上表达，具有与两者相关的能力。 SHP-1 和 SHP-2 以酪氨酸磷酸化依赖性方式进行。在本研究中，我们使用引入野生型 (WT) 或 ITIM-less 突变体 (YF) cDNA 的小鼠探讨了 Ly49Q 在中性粒细胞粘附和迁移中的作用在体外和体内没有炎症刺激的情况下，Ly49Q-WT（而非 Ly49Q-YF）通过防止粘着斑形成来抑制牢固粘连和扩散。 Ly49Q 可以防止稳态条件下的危险粘附，Ly49Q-YF 的表达无法发挥 ITIM 依赖性信号，导致早期中性粒细胞浸润减少，这是由于组织缺陷所致。相反，Ly49Q-WT 通过增强 Ly49Q 的表达来增强中性粒细胞浸润。此外，Ly49Q-WT（而非 Ly49Q-YF 小鼠）会自发出现外周淋巴器官出血，并伴有中性粒细胞增加。Ly49Q 的这些功能似乎是通过调节趋化刺激物中相关 SHP-1 的细胞内定位来介导的。因此，中性粒细胞上的 Ly49Q 不仅是稳定状态下稳态调节的关键分子。但炎症时也急迁移。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Introduction of Sd(a) carbohydrate antigen in gastrointestinal cancer cells eliminates selectin ligands and inhibits metastasis.

在胃肠道癌细胞中引入 Sd(a) 碳水化合物抗原可消除选择素配体并抑制转移。

DOI：
发表时间：
2005
期刊：
Cancer Re& 65
影响因子：
0
作者：
Kawamura;Y.I.;et al.
通讯作者：
et al.

Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling.

DOI：
10.1084/jem.20041817
发表时间：
2005-02-07
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
Shinohara H;Inoue A;Toyama-Sorimachi N;Nagai Y;Yasuda T;Suzuki H;Horai R;Iwakura Y;Yamamoto T;Karasuyama H;Miyake K;Yamanashi Y
通讯作者：
Yamanashi Y

Recognition of H-2Kb by Ly49Q suggests a role for class Ia MHC regulation of plasmacytoid dendritic cells.

Ly49Q 对 H-2Kb 的识别表明 Ia 类 MHC 对浆细胞样树突状细胞的调节作用。