The S1P-analog FTY720 differentially modulates T-cell homing via HEV:: T-cell-expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer patches
The S1P-analog FTY720 differentially modulates T-cell homing via HEV:: T-cell-expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer patches
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DOI：
10.1182/blood-2004-09-3687
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发表时间：
2005-08-15
期刊：
影响因子：
20.3
通讯作者：
von Andrian, UH
中科院分区：
文献类型：
--
作者：
Halin, C;Scimone, ML;von Andrian, UH
鞘氨醇-1-磷酸（S1P）及其受体S1P控制t细胞从胸腺和次级淋巴器官（slo）的分泌。为了进一步确定S1P在淋巴细胞运输中的作用，我们使用S1P(1)（-/-）淋巴细胞和受体野生型（WT）小鼠进行了过继性转移实验和活体显微镜（IVM）。FTY720是一种下调S1P受体的免疫抑制剂。通过多光子IVM评估，S1P、缺乏和FTY720导致T细胞从血液中迅速消失，在slo中滞留时间延长，并在骨髓中积累，但不会改变周围淋巴结（pln）间质T细胞的运动。然而，S1P(1)（-/-）淋巴细胞由于整合素介导的高内皮小静脉（hev）的firm arrest减弱而显示出短期内对pln的归巢减少。相比之下，S1P(1)(-/-) T细胞正常归巢到Peyer斑块（PPs），而S1P(1)(-/-) B细胞在归巢到PPs方面有明显缺陷，并且在PP hev中阻滞较差。因此，S1P不仅控制淋巴细胞从slo中退出，还促进了组织和亚群特异性整合素在归巢过程中的激活。有趣的是，FTY720处理通过增强整合素介导的hev阻滞，增强了PPs中S1P(1)充足和S1P(1)(-/-) T细胞的积累。因此，FTY720对不依赖于t细胞表达的S1P的PPs中的t细胞转运具有独特的影响(1)。
Sphingosine-1-phosphate (S1P) and its receptor S1P, control T-cell egress from thymus and secondary lymphoid organs (SLOs). To further define the role of S1P, in lymphocyte trafficking, we performed adoptive transfer experiments and intravital microscopy (IVM) using both S1P(1)(-/-) lymphocytes and recipient wild-type (WT) mice treated with FTY720, an immunosuppressant that downmodulates S1P receptors. S1P, deficiency and FTY720 caused rapid disappearance of T cells from blood, prolonged retention in SLOs, and accumulation in bone marrow, but did not alter interstitial T-cell motility in peripheral lymph nodes (PLNs) as assessed by multiphoton IVM. However, S1P(1)(-/-) lymphocytes displayed reduced short-term homing to PLNs due to attenuated integrin-mediated firm arrest in high endothelial venules (HEVs). By contrast, S1P(1)(-/-) T cells homed normally to Peyer patches (PPs), whereas S1P(1)(-/-) B cells had a marked defect in homing to PPs and arrested poorly in PP HEVs. Therefore, S1P, not only controls lymphocyte egress from SLOs, but also facilitates in a tissue- and subset-specific fashion integrin activation during homing. Interestingly, FTY720 treatment enhanced accumulation of both S1P(1) sufficient and S1P(1)(-/-) T cells in PPs by enhancing integrin-mediated arrest in HEVs. Thus, FTY720 exerts unique effects on T-cell traffic in PPs that are independent of T-cell-expressed S1P(1).