Rapid induction of medullary thymocyte phenotypic maturation and egress inhibition by nanomolar sphingosine 1-phosphate receptor agonist
Rapid induction of medullary thymocyte phenotypic maturation and egress inhibition by nanomolar sphingosine 1-phosphate receptor agonist
复制标题
DOI：
10.1073/pnas.1832725100
复制
发表时间：
2003-09-16
影响因子：
11.1
通讯作者：
McHeyzer-Williams, MG
中科院分区：
文献类型：
--
作者：
Rosen, H;Alfonso, C;McHeyzer-Williams, MG
每天只有少量的胸腺中产生的T细胞被选择来补充外周T细胞池。关于胸腺选择的研究已知之甚多，但对调节骨髓成熟和成熟T细胞释放到血液中的机制知之甚少。在这里，我们证明了通过1-磷酸鞘氨醇（S1 P）受体激动剂诱导的CD 69的丢失快速加速胸腺髓质细胞表型成熟。低纳摩尔激动剂浓度选择性诱导CD 69（int）CD 62 L（high）单阳性T细胞的变化，导致CD 69在2小时内下调。虽然CD 69损失加速，但成熟T细胞进入血液的出口在2小时内被抑制>95%。这两个过程表现出平行的敏感性和剂量反应。总之，这些数据揭示了一种有效的手段，用于快速调节胸腺出口，其中S1 P受体激动剂改变了胸腺细胞在胸腺成熟后期的表型成熟和进入血液的出口。现在显示S1 P系统急性调节胸腺和淋巴结出口。抑制淋巴细胞从胸腺和淋巴结流出可通过破坏外周T细胞的再循环而协同地有助于临床上有用的免疫抑制。
Only a small number of T cells generated in the thymus each day are selected to replenish the peripheral T cell pool. Much is known about thymic selection; however, little is known of the mechanisms regulating medullary maturation and the release of mature T cells into the blood. Here we demonstrate a rapid acceleration of medullary thymocyte phenotypic maturation through loss of CD69 induced by sphingosine 1-phosphate (S1P) receptor agonist. Low nanomolar agonist concentrations selectively induce changes in CD69(int) CD62L(high) single positive T cells, resulting in down-modulation of CD69 within 2 h. While CD69 loss is accelerated, egress of mature T cells into blood is inhibited >95% within 2 h. Both processes exhibit parallel sensitivities and dose-responses. Together, these data reveal a potent means for rapidly regulating thymic export where S1P receptor agonism alters both phenotypic maturation and egress of thymocytes into blood during late thymic maturation. The S1P system is now shown to acutely regulate both thymic and lymph node egress. Inhibition of lymphocyte egress from thymus and lymph node can contribute synergistically to clinically useful immunosupression by disrupting recirculation of peripheral T cells.