Sci. Immunol. 4, eaav1263 (2019)

Sphingosine 1-phosphate (S1P) regulates lymphocyte trafficking. In Science Immunology, Xiong et al. show that S1P receptors (S1PRs) serve distinct roles during the migration of CD4+ T cells across lymphatic endothelial cell (LEC) barriers into the afferent lymphatics. LECs express S1PR2, which responds to S1P by upregulating expression of the adhesion molecule VCAM-1 and altering expression of cellular junction proteins, including VE-cadherin, occludin and zonulin-1. Mouse and human CD4+ effector and memory T cells express S1PR1 and S1PR4. Inhibition or disruption of S1PR1, S1PR4 or S1PR2 diminishes the migration of T cells to S1P both in vitro and in vivo, but not their migration to the chemokine receptor CCR7 ligand CCL19. Inhibition of S1P signaling blunts early interactions of T cells with LECs, although S1PR1 seems to function differently from S1PR4. Interestingly, S1P-dependent signaling preferentially affects the transcellular migration of T cells through LECs rather than their paracellular trafficking. Thus, S1P governs distinct steps in the trafficking of T cells into the afferent lymphatics.