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Regulation of immune cell trafficking by adhesion molecules and immune responses

粘附分子和免疫反应调节免疫细胞运输

基本信息

批准号：
16043224
负责人：
KINASHI Tatsuo
金额：
$ 25.34万
依托单位：
Kansai Medical University (2005-2006)Kyoto University (2004)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16043224/
关键词：
integrin lymphocyte homing RapL RAPL Mst1 cell migration cell polarity LFA-1 免疫応答シグナル伝達リンパ球ホーミング ICAM-1

项目摘要

Dynamic regulation of immune cell trafficking is central to immuno-surveillance. Motile lymphocyte is a fundamental component regulating this process. Our understanding of lymphocyte trafficking has been facilitated by identification of chemokines and adhesion molecules such as LFA-1 and a4 integrins, which play important roles in mediating transmigration through endothelium and antigen recognition. We have shown that small GTPase Rap1 regulates integrin-mediated adhesion and promotes lymphocyte adhesive responses and migration. In this study, we showed that a novel Rap1 effector RAPL positively regulated integrin-mediated adhesion triggered by chemokines and specific antigen, depending on Rapl. Rap1/RAPL signaling coordinately regulates integrin distribution and cell polarity, thereby generates lymphocyte robust migration. We further identified Mstl (STK4) belonging to the Ste20-related serine/threonine kinase family. Upon binding to Rap1-GTP, RAPL physically bound to Mstl through the … More coiled-coil domain of RAPL, and increased Mstl kinase activities. Activated Mstl mediated LFA-1 surface clustering induced by chemokine and TCR crosslinking. RAPL and Mstl were exclusively co-fractionated in light-density compartments enrich for vesicle components containing LFA-1 and Rap1 by sucrose-density centrifugation, suggesting RAPL and Mstl regulate intracellular vesicle transport of LFA-1. In order to investigate physiological roles of RAPL signaling in vivo, we generated RAPL-deficient mice. RAPL-deficient lymphocytes were defective in stable adhesion to the high endothelium, leading to inefficient entry into tissues, resulting hypocellularity of secondary lymph nodes. In addition, we found that dendritic antigen-presenting cells abundantly expressed RAPL. RAPL-deficient skin dendritic cells were impaired in migration to draining lymph nodes upon inflammation. Collectively, we demonstrate that RAPL signaling plays critical roles in in vivo trafficking of lymphocytes and dendritic cells essential for immunosurveillance through regulating integrin-mediated adhesive behaviors. Less

免疫细胞运输的动态调节是免疫监视的核心。运动淋巴细胞是调节这一过程的基本组成部分。我们对淋巴细胞运输的理解已经通过鉴定趋化因子和粘附分子如LFA-1和α 4整联蛋白而得到促进，所述趋化因子和粘附分子在通过内皮和抗原识别介导迁移中起重要作用。我们已经表明，小GTTRAP 1调节整合素介导的粘附，促进淋巴细胞粘附反应和迁移。在这项研究中，我们发现了一种新的Rap 1效应器RAPL正调控整合素介导的粘附触发的趋化因子和特异性抗原，依赖于Rap 1。Rap 1/RAPL信号传导协调调节整合素分布和细胞极性，从而产生淋巴细胞稳健的迁移。我们进一步鉴定了属于Ste 20相关的丝氨酸/苏氨酸激酶家族的Mstl（STK 4）。在与Rap 1-GTP结合后，RAPL通过Mstl结合位点与Mstl物理结合。 ...更多信息 RAPL的卷曲螺旋结构域，并增加Mstl激酶活性。活化的Mstl介导由趋化因子和TCR交联诱导的LFA-1表面聚集。RAPL和Mstl专门共分馏在轻密度室丰富的囊泡成分含有LFA-1和Rap 1的蔗糖密度离心，表明RAPL和Mstl调节细胞内囊泡运输的LFA-1。为了研究体内RAPL信号传导的生理作用，我们产生了RAPL缺陷小鼠。RAPL缺陷型淋巴细胞在与高内皮细胞的稳定粘附方面存在缺陷，导致进入组织的效率低下，从而导致次级淋巴结的细胞减少。此外，我们发现树突状抗原呈递细胞大量表达RAPL。RAPL缺陷的皮肤树突状细胞在炎症后迁移到引流淋巴结时受损。总的来说，我们证明了RAPL信号在体内淋巴细胞和树突状细胞的运输中起着至关重要的作用，通过调节整合素介导的粘附行为对免疫监视至关重要。少