S1P Lyase Regulation of Thymic Egress and Oncogenic Inflammatory Signaling

Figure 3

Egress of mature thymocytes from the thymus. Double-positive (DP) CD4⁺ and CD8⁺ thymocytes migrate from the thymic cortex to the medulla, where they differentiate into CD4⁺ and CD8⁺ single-positive (SP) thymocytes. As these cells mature, they express S1P lyase (SPL) and the transcriptional factor KLF2. The latter leads to increase transcription of its target gene, s1pr1, resulting in a high expression of surface S1PR1. Perivascular and endothelial cells in the corticomedullary region secrete S1P. Thymic dendritic and medullary thymic epithelial cells remove extracellular S1P by irreversible degradation or dephosphorylation to sphingosine, respectively. The resulting small S1P gradient interacts with the S1PR1 on the mature thymocytes. Prior to exit, S1PR1 receptors undergo multiple cycles of internalization to finally exit into the blood where there is a high S1P concentration. The high S1P concentration leads to S1PR1 permanent internalization and degradation.