S1P1 receptor signaling overrides retention mediated by Gαi-coupled receptors to promote T cell egress
S1P1 receptor signaling overrides retention mediated by Gαi-coupled receptors to promote T cell egress
复制标题
DOI：
10.1016/j.immuni.2007.11.017
复制
发表时间：
2008-01-01
期刊：
影响因子：
32.4
通讯作者：
Cyster, Jason G.
中科院分区：
文献类型：
--
作者：
Pham, Trung H. M.;Okada, Takaharu;Cyster, Jason G.
鞘氨醇-1-磷酸受体-1（S1 P（1））促进淋巴细胞从淋巴器官排出的机制尚未明确。在这里，我们发现CCR 7缺陷型T细胞比野生型细胞更快地离开淋巴结，而CCR 7过表达细胞保留更长时间。在用FTY 720（一种引起淋巴细胞S1 P下调的激动剂）处理后，CCR 7缺陷型T细胞的保留效果不如野生型T细胞。此外，用百日咳毒素处理通过G α（i）蛋白偶联受体传递的IL-6信号，恢复了S1 P（1）缺陷淋巴细胞的外出能力。我们还发现，淋巴结皮质窦状隙中的T细胞聚集需要内在的S1 P（1）表达，并被CCR 7拮抗。这些发现提示了一种模型，其中S1 P（1）在淋巴细胞中发挥作用，通过克服由CCR 7和额外的G α（i）偶联受体介导的滞留信号来促进淋巴结排出。此外，通过同时上调S1 P（1）和下调CCR 7，已经分裂多次的T细胞切换到有利于外出而不是滞留的状态。
The mechanism by which sphingosine-1-phosphate receptor-1 (S1P(1)) acts to promote lymphocyte egress from lymphoid organs is not defined. Here, we showed that CCR7-deficient T cells left lymph nodes more rapidly than wild-type cells did, whereas CCR7-overexpressing cells were retained for longer. After treatment with FTY720, an agonist that causes down-modulation of lymphocyte S1P(1), CCR7-deficient T cells were less effectively retained than wild-type T cells. Moreover, treatment with pertussis toxin to inactivate signaling via G alpha(i)-protein-coupled receptors restored egress competence to S1P(1)-deficient lymphocytes. We also found that T cell accumulation in lymph node cortical sinusoids required intrinsic S1P(1) expression and was antagonized by CCR7. These findings suggest a model where S1P(1) acts in the lymphocyte to promote lymph node egress by overcoming retention signals mediated by CCR7 and additional G alpha(i)-coupled receptors. Furthermore, by simultaneously upregulating S1P(1) and downregulating CCR7, T cells that have divided multiple times switch to a state favoring egress over retention.