Lan Yuk Yuen, Tokita Daisuke, Wang Zhiliang, Wang Hao Chen, Zhan Jianghua, Brinkmann Volker, Thomson Angus W
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Transpl Immunol. 2008 Nov;20(1-2):88-94. doi: 10.1016/j.trim.2008.07.004. Epub 2008 Aug 9.
The novel immunomodulator FTY720 is a prototypic sphingosine-1-phosphate (S1P) receptor agonist that regulates lymphocyte migration and prolongs allograft survival. Skin dendritic cells (DC) play important roles in cutaneous immunity. We investigated the migration and function of skin DC exposed to FTY720 in vivo, or to its metabolite FTY720 phosphate (P) in vitro. C57BL/10 (H2(b)) recipient (but not donor) FTY720 treatment prolonged median skin C3H (H2(k)) allograft survival significantly, from 12 to 34.5 days. Non-transplanted, FTY720-treated mice revealed a marked increase in skin DC, although total DC in skin-draining lymph nodes (DLN) were unchanged compared with controls. Fewer allogeneic donor DC migrated to DLN of FTY720-treated graft recipients. DC that migrated from the skin of FTY720-treated mice showed reduced MHC class II, CD86 and CCR7 expression, suggesting impaired migratory potential to secondary lymphoid tissue, that correlated with DC retention in skin, and reduced T cell stimulatory activity. Fewer DC migrated from normal skin explants exposed to the FTY720 metabolite, FTY720P than to control medium. DC that did migrate expressed lower levels of MHC class II, CD86 and CCR7, and inferior T cell stimulatory ability. These data demonstrate S1P signaling regulates skin DC trafficking and modulates MHC class II, costimulatory, and homing receptor molecule expression that impairs their ability to elicit allogeneic T cell responses.
新型免疫调节剂FTY720是一种典型的1-磷酸鞘氨醇（S1P）受体激动剂，可调节淋巴细胞迁移并延长同种异体移植物存活时间。皮肤树突状细胞（DC）在皮肤免疫中发挥重要作用。我们研究了体内暴露于FTY720或体外暴露于其代谢产物磷酸化FTY720（P）的皮肤DC的迁移和功能。用FTY720处理C57BL/10（H2(b)）受体（而非供体）可显著延长C3H（H2(k)）皮肤同种异体移植物的中位存活时间，从12天延长至34.5天。未移植的FTY720处理小鼠皮肤DC显著增加，尽管与对照组相比，皮肤引流淋巴结（DLN）中的总DC数量未变。迁移至FTY720处理的移植物受体DLN的同种异体供体DC较少。从FTY720处理小鼠皮肤迁移的DC显示MHC II类分子、CD86和CCR7表达降低，提示其迁移至次级淋巴组织的潜能受损，这与DC在皮肤中的滞留以及T细胞刺激活性降低相关。与对照培养基相比，暴露于FTY720代谢产物FTY720P的正常皮肤外植体迁移出的DC较少。确实迁移的DC表达较低水平的MHC II类分子、CD86和CCR7，且T细胞刺激能力较差。这些数据表明S1P信号传导调节皮肤DC的 trafficking，并调节MHC II类分子、共刺激分子和归巢受体分子的表达，从而损害其引发同种异体T细胞反应的能力。
