CD4 T cell sphingosine 1-phosphate receptor (S1PR)1 and S1PR4 and endothelial S1PR2 regulate afferent lymphatic migration

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Science Immunology  15 Mar 2019:
Vol. 4, Issue 33, eaav1263
DOI: 10.1126/sciimmunol.aav1263

Getting immune cells home

Immune cells are recruited to tissues from the lymphatic system via efferent lymphatics in response to insults ranging from skin allergies to flu infection. Immune cells recirculate back to draining lymph nodes via afferent lymphatics. Using a combination of in vitro systems and in vivo studies, Xiong et al. have examined the role of sphingosine 1-phosphate (S1P) and its receptors (S1PRs) in the egress of T cells from tissues. They found expression of S1PR1 and S1PR4 on T cells and engagement of S1PR2 on lymphatic endothelial cells to be important for this process. Whereas the role of S1PRs in recruitment of lymphocytes to tissues is well established, the current study extends their importance to recirculation of immune cells back to the lymphatic system.


Sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs) regulate migration of lymphocytes out of thymus to blood and lymph nodes (LNs) to efferent lymph, whereas their role in other tissue sites is not known. Here, we investigated the question of how these molecules regulate leukocyte migration from tissues through afferent lymphatics to draining LNs (dLNs). S1P, but not other chemokines, selectively enhanced human and murine CD4 T cell migration across lymphatic endothelial cells (LECs). T cell S1PR1 and S1PR4, and LEC S1PR2, were required for migration across LECs and into lymphatic vessels and dLNs. S1PR1 and S1PR4 differentially regulated T cell motility and vascular cell adhesion molecule–1 (VCAM-1) binding. S1PR2 regulated LEC layer structure, permeability, and expression of the junction molecules VE-cadherin, occludin, and zonulin-1 through the ERK pathway. S1PR2 facilitated T cell transcellular migration through VCAM-1 expression and recruitment of T cells to LEC migration sites. These results demonstrated distinct roles for S1PRs in comodulating T cell and LEC functions in migration and suggest previously unknown levels of regulation of leukocytes and endothelial cells during homeostasis and immunity.

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