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

Abstract

Sphingosine 1-phosphate (S1P) and S1P receptors (S1PR) regulate migration of lymphocytes out of thymus to blood and lymph nodes (LN) to efferent lymph, while 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 lymph node (dLN). S1P, but not other chemokines, selectively enhanced human and murine CD4 T cell migration across lymphatic endothelial cells (LEC). T cell S1PR1 and S1PR4, and LEC S1PR2, were required for migration across LEC and into lymphatic vessels and dLN. S1PR1 and S1PR4 differentially regulated T cell motility and 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 co-modulating T cell and LEC functions in migration and suggest new levels of regulation of leukocytes and endothelial cells during homeostasis and immunity.

S1PR4 ablation reduces tumor growth and improves chemotherapy via CD8+ T cell expansion

“…Our data thus indicate that S1PR4 might be an interesting target, particularly in combination with conventional therapy. S1PR4 is expressed at high levels mainly by lymphocytes and neutrophils, although S1PR4 was recently shown to play a role in CD4 + T cell transmigration in a lymphatic context (41). However, S1PR4-deficient mice did not show defects in lymphocyte composition in lymphatic organs, as shown in this and another study (42).…”

Lysolipid receptor cross-talk regulates lymphatic endothelial junctions in lymph nodes

“…In endothelial cells, cell-surface signaling of S1PR1 regulates vascular barrier function (Lee et al, 1999; Oo et al, 2007). However, S1PR2, which activates the Rho GTPase, disrupts the endothelial barrier (Sanchez et al, 2007), and its function in collecting LECs is needed for lymphocyte trafficking from tissues to the lymph nodes (Xiong et al, 2019). Thus, our finding that LPAR1 modulates S1PR1 directly suggests functional cross-talk between LPA and S1P.…”

The lymph node stromal laminin α5 shapes alloimmunity

“…CCL21 and CXCL12 mRNA increased in FRCs but not in BECs and LECs ( Figure 3A). FRCs express intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and mucosal vascular addressin cell adhesion molecule-1 (MAd-CAM-1), which play important roles in T cell migration (32). In the LNs of Lama5-KO mice, VCAM-1 protein expression was increased in the CR and around HEVs, and the mRNAs encoding VCAM-1 and ICAM-1, but not MadCAM-1, were increased in FRCs ( Figure 3, B and C).…”