Matloubian Mehrdad, Lo Charles G, Cinamon Guy, Lesneski Matthew J, Xu Ying, Brinkmann Volker, Allende Maria L, Proia Richard L, Cyster Jason G
Howard Hughes Medical Institute and Department of Microbiology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, California 94143-0414, USA.
Nature. 2004 Jan 22;427(6972):355-60. doi: 10.1038/nature02284.
Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
适应性免疫依赖于T细胞从胸腺中输出，以及T细胞和B细胞在二级淋巴器官之间穿梭以搜寻抗原。在淋巴器官中被激活后，T细胞必须再次回到循环系统以到达感染部位；然而，调节淋巴器官输出的机制尚不清楚。一种免疫抑制剂药物FTY720可抑制淋巴细胞从淋巴器官中迁出，磷酸化的FTY720可结合并激活已知的5种1-磷酸鞘氨醇（S1P）受体中的4种。然而，S1P受体在正常免疫细胞迁移中的作用尚不清楚。在此我们表明，在造血细胞缺乏单一S1P受体（S1P1，也称为Edg1）的小鼠中，外周没有T细胞，因为成熟T细胞无法离开胸腺。虽然B细胞存在于外周淋巴器官中，但它们在血液和淋巴中严重缺乏。过继性细胞转移实验证实，T细胞和B细胞离开淋巴器官对S1P1有内在需求。此外，在T细胞从胸腺中输出之前的发育过程中，依赖S1P1的趋化反应性被强烈上调，而在周围淋巴细胞激活过程中S1P1被下调，这与T细胞滞留在淋巴器官中有关。我们发现，FTY720处理可下调S1P1，在淋巴细胞中产生一种暂时的药理学上的S1P1缺失状态，这就为FTY720诱导淋巴细胞滞留的机制提供了解释。这些发现证实，S1P1对淋巴细胞再循环至关重要，并且它调节从胸腺和外周淋巴器官的输出。
