Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1
Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1
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DOI：
10.1038/nature02284
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发表时间：
2004-01-22
期刊：
影响因子：
64.8
通讯作者：
Cyster, JG
中科院分区：
文献类型：
--
作者：
Matloubian, M;Lo, CG;Cyster, JG
适应性免疫依赖于T细胞从胸腺中排出，T和B细胞在次级淋巴器官之间移动以寻找抗原。在淋巴器官中激活后，T细胞必须再次返回循环以到达感染部位;然而，调节淋巴器官退出的机制尚不清楚。一种免疫抑制药物FTY 720可抑制淋巴细胞从淋巴器官中移出，磷酸化FTY 720可结合并激活五种已知鞘氨醇-1-磷酸（S1P）受体中的四种（1 - 4）。然而，S1P受体在正常免疫细胞运输中的作用尚不清楚。在这里，我们发现，在造血细胞缺乏单一S1P受体（S1P（1）;也称为Edg 1）的小鼠中，外周中没有T细胞，因为成熟的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。连续性细胞转移实验确定了淋巴器官排出对T和B细胞中S1 P（1）的内在要求。此外，S1P（1）依赖性趋化反应在T细胞发育中在离开胸腺之前强烈上调，而S1P（1）在外周淋巴细胞活化期间下调，这与淋巴器官中的滞留有关。我们发现FTY720治疗下调S1P（1），在淋巴细胞中产生暂时的药理学S1P（1）-无效状态，为FTY720诱导的淋巴细胞隔离机制提供了解释。这些发现证实了S1P（1）对淋巴细胞再循环是必需的，并且它调节从胸腺和外周淋巴器官的排出。
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(1-4). 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 ( S1P(1); 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 S1P(1) in T and B cells for lymphoid organ egress. Furthermore, S1P(1)- dependent chemotactic responsiveness is strongly upregulated in T- cell development before exit from the thymus, whereas S1P(1) is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P(1), creating a temporary pharmacological S1P(1)- null state in lymphocytes, providing an explanation for the mechanism of FTY720- induced lymphocyte sequestration. These findings establish that S1P(1) is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.