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

Yanbao Xiong, Wenji Piao, C. Colin Brinkman, Lushen Li, Joseph M. Kulinski, Ana Olivera, Andreane Cartier, Timothy Hla, Keli L. Hippen, Bruce R. Blazar, Susan R. Schwab, Jonathan S. Bromberg

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63 Scopus citations


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.

Original languageEnglish (US)
Article numbereaav1263
JournalScience Immunology
Issue number33
StatePublished - Mar 15 2019

Bibliographical note

Funding Information:
This study was supported by R01AI062765 and AI114496 (to J.S.B.); Division of Intramural Research Programs, NIAID (to A.O.); R35 HL135821 (to T.H.); RO1 HL11879 (to B.R.B.); and R01AI085166 and R01AI123308 (to S.R.S.).

Publisher Copyright:
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works


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