Saba Julie D
University of California San Francisco Benioff Children's Hospital Oakland, Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94611 USA.
J Immunol Sci. 2017;1(1):1-8. doi: 10.29245/2578-3009/2018/1.1103. Epub 2017 Dec 6.
After undergoing positive and negative selection in the thymus, surviving mature T cells egress from the thymic parenchyma and enter the bloodstream to participate in adaptive immunity. Thymic egress requires signals mediated by sphingosine-1-phosphate (S1P), a bioactive lipid that serves as the ligand for a family of G protein-coupled receptors (S1P1-5) expressed on many cell types, including T cells. In the final stage of their development, T cells upregulate S1P1 expression on the cell surface, which enables them to recognize and respond to a chemotactic S1P gradient that lures them into the bloodstream. The gradient is generated by an S1P source close to the site of egress combined with an S1P sink generated by the actions of S1P catabolic enzymes including S1P lyase (SPL), the only enzyme that irreversibly degrades S1P. The requisite contribution of SPL to thymic egress is demonstrated by the profound lymphopenia observed in SPL knockout (KO) mice and wild type mice treated with SPL inhibitors. SPL is robustly expressed in thymic epithelial cells (TECs), which make up the stromal reticular network of the thymus. However, TEC SPL was recently found to be dispensable for thymic egress. In contrast, deletion of SPL in dendritic cells (DCs) - which represent only a small percent of thymic stroma - disrupts the S1P gradient and blocks thymic egress. These recent observations identify DCs as homeostatic regulators of thymic export through the actions of SPL, thereby adding one more piece to the complex puzzle of how S1P signaling contributes to the regulation of T cell trafficking.
在胸腺中经历阳性和阴性选择后，存活的成熟T细胞从胸腺实质中逸出并进入血液循环，参与适应性免疫。胸腺输出需要由1-磷酸鞘氨醇（S1P）介导的信号，S1P是一种生物活性脂质，作为许多细胞类型（包括T细胞）上表达的G蛋白偶联受体家族（S1P1 - 5）的配体。在其发育的最后阶段，T细胞上调细胞表面的S1P1表达，这使它们能够识别并响应趋化性S1P梯度，该梯度将它们吸引到血液循环中。该梯度由靠近输出部位的S1P源与由包括S1P裂解酶（SPL）在内的S1P分解代谢酶的作用产生的S1P汇共同产生，SPL是唯一不可逆降解S1P的酶。在SPL基因敲除（KO）小鼠和用SPL抑制剂处理的野生型小鼠中观察到的严重淋巴细胞减少症证明了SPL对胸腺输出的必要作用。SPL在胸腺上皮细胞（TEC）中大量表达，TEC构成胸腺的基质网状网络。然而，最近发现TEC中的SPL对于胸腺输出是可有可无的。相比之下，在仅占胸腺基质一小部分的树突状细胞（DC）中删除SPL会破坏S1P梯度并阻断胸腺输出。这些最新观察结果通过SPL的作用将DC鉴定为胸腺输出的稳态调节因子，从而为S1P信号传导如何促进T细胞运输调节的复杂谜题又增添了一块。
