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

• 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

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

抑制性受体通过对细胞功能的负性调节，在免疫反应的精细调控和终止中起着至关重要的作用。已经在不同类型的细胞上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经得到了很好的表征。抑制性NK受体对靶细胞表面MHC-I类或相关分子的识别使NK细胞既能阻止自身杀伤，又能破坏MHC-I类分子水平降低的不适当细胞。Ly49Q是一种携带ITIM的抑制性受体，属于Ly49家族，是NK受体的一个亚家族。虽然Ly49Q与Ly49家族有很高的结构相似性和染色体定位，但Ly49Q具有不同于Ly49家族其他成员的独特功能。Ly49Q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。Ly49Q拥有英博…在这项研究中，我们利用野生型(WT)或ITIM缺失突变体(YF)的小鼠，在体外和体内研究了Ly49Q在中性粒细胞黏附和迁移中的作用。在没有炎症刺激的情况下，Ly49Q-WT而不是Ly49Q-YF通过阻止局部粘连的形成来抑制牢固的粘连和扩散，这表明Ly49Q在稳态条件下防止了危险的粘连。在炎症状态下，不能传递ITIM依赖信号的Ly49Q-YF的表达导致早期中性粒细胞在组织中的浸润减少。这是由于对fMLP反应的细胞极性的组织缺陷所致。相反，Ly49Q-WT通过增强Ly49Q的表达而增加中性粒细胞的渗透。此外，Ly49Q-WT小鼠，而不是Ly49Q-YF小鼠，自发性地出现外周淋巴器官出血，并伴随着中性粒细胞的增加。Ly49Q的这些功能似乎是通过调节相关的SHP-1在趋化刺激中的细胞内定位和通过改变自身的细胞内定位来调节ITIM依赖的方式来实现的。因此，中性粒细胞上的Ly49Q不仅是调节稳态内稳态调节的关键分子，也是调节炎症时的紧急迁移的关键分子。较少

项目成果

Development of murine plasmacytoid dendritic cells defined by increased expression of an inhibitory NK receptor, Ly49Q

• DOI: 10.4049/jimmunol.174.11.6657
• 发表时间: 2005-06-01
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Omatsu, Y;Iyoda, T;Inaba, K
• 通讯作者: Inaba, K

Ly49B is expressed on multiple subpopulations of myeloid cells

• DOI: 10.4049/jimmunol.177.9.5840
• 发表时间: 2006-11-01
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Gays, Frances;Aust, Jonathan G.;Brooks, Colin G.
• 通讯作者: Brooks, Colin G.

Predominant T helper type 2-inflammatory responses promote murine colon cancers

• DOI: 10.1002/ijc.21639
• 发表时间: 2006-05-01
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Osawa, E;Nakajima, A;Dohi, T
• 通讯作者: Dohi, T

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。

• 发表时间: 2005
• 期刊: Cancer Re& 65
• 作者: Kawamura;Y.I.;et al.
• 通讯作者: et al.

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

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

• 发表时间: 2007
• 期刊: Mol. Immunol. 44
• 作者: Koyanagi M;et. al.;Toyama-Sorimachi N(8番目:全10名);Toyama-Sorimachi N(4番目:全8名);Toyama-Sorimachi N(7番目:全9名)
• 通讯作者: Toyama-Sorimachi N(7番目:全9名)