Rolling of Th1 cells via p-selectin glycoprotein ligand-1 stimulates LFA-1-Mediated cell binding to ICAM-1
Rolling of Th1 cells via p-selectin glycoprotein ligand-1 stimulates LFA-1-Mediated cell binding to ICAM-1
复制标题
DOI：
10.4049/jimmunol.174.3.1424
复制
发表时间：
2005-02-01
影响因子：
4.4
通讯作者：
Miyasaka, M
中科院分区：
文献类型：
--
作者：
Atarashi, K;Hirata, T;Miyasaka, M
活化的T细胞从血液中迁移到非淋巴组织，通过一个多步骤的过程，涉及细胞滚动，逮捕，和transmigration。P-Selectin glycoprotein ligand-1（PSGL-1）是P-选择素的主要配体，在活化的T细胞亚群如Th 1细胞上表达，并介导血管内皮上的细胞滚动。滚动细胞通过整合素介导的牢固粘附步骤被阻止。尽管内皮上存在的趋化因子触发整联蛋白活化，但是已经提出了第二种机制，其中通过滚动受体的信号传导直接活化整联蛋白。在这项研究中，我们表明，抗体介导的交联的PSGL-1的Th 1细胞增强LFA-1依赖性细胞与ICAM-1的结合。PSGL-1交联不增强可溶性ICAM-1结合，但诱导LFA-1在细胞表面上的聚集，表明LFA-1亲合力的增加可能是与ICAM-1结合增强的原因。PSGL-1交联和Th 1刺激趋化因子CXCL 10或CCL 5的组合刺激对LFA-1介导的Th 1细胞粘附以及对LFA-1在细胞表面上的再分布显示出超过加和效应。此外，PSGL-1介导的P-选择素滚动增强了Th 1细胞在ICAM-1上的聚集。PSGL-1交联诱导蛋白激酶C亚型的活化，并且在流动和静态条件下观察到的增加的Th 1细胞粘附被钙磷蛋白C强烈抑制，暗示蛋白激酶C在PSGL-1介导的LFA-1活化的细胞内信号传导中。这些结果支持PSGL-1介导的滚动相互作用诱导细胞内信号，导致整合素激活，促进Th 1细胞停滞和随后迁移到靶组织的想法。
Activated T cells migrate from the blood into nonlymphoid tissues through a multistep process that involves cell rolling, arrest, and transmigration. P-Selectin glycoprotein ligand-1 (PSGL-1) is a major ligand for P-selectin expressed on subsets of activated T cells such as Th1 cells and mediates cell rolling on vascular endothelium. Rolling cells are arrested through a firm adhesion step mediated by integrins. Although chemokines presented on the endothelium trigger integrin activation, a second mechanism has been proposed where signaling via rolling receptors directly activates integrins. In this study, we show that Ab-mediated crosslinking of the PSGL-1 on Th1 cells enhances LFA-1-dependent cell binding to ICAM-1. PSGL-1 cross-linking did not enhance soluble ICAM-1 binding but induced clustering of LFA-I on the cell surface, suggesting that an increase in LFA-1 avidity may account for the enhanced binding to ICAM-1. Combined stimulation by PSGL-1 cross-linking and the Th1-stimulating chemokine CXCL10 or CCL5 showed a more than additive effect on LFA-1-mediated Th1 cell adhesion as well as on LFA-1 redistribution on the cell surface. Moreover, PSGL-1-mediated rolling on P-selectin enhanced the Th1 cell accumulation on ICAM-1 under flow conditions. PSGL-1 cross-linking induced activation of protein kinase C isoforms, and the increased Th1 cell adhesion observed under flow and also static conditions was strongly inhibited by calphostin C, implicating protein kinase C in the intracellular signaling in PSGL-1-mediated LFA-1 activation. These results support the idea that PSGL-1-mediated rolling interactions induce intracellular signals leading to integrin activation, facilitating Th1 cell arrest and subsequent migration into target tissues.