Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses.
Sphingosine 1-phosphate type 1 (S1P(1)) receptor agonists cause sequestration of lymphocytes in secondary lymphoid organs by a mechanism that is not well understood. One hypothesis proposes that agonists act as 'functional antagonists' by binding and internalizing S1P(1) receptors on lymphocytes; a second hypothesis proposes instead that S1P(1) agonists act on endothelial cells to prevent lymphocyte egress from lymph nodes. Here, two-photon imaging of living T cells in explanted lymph nodes after treatment with S1P(1) agonists or antagonists has provided insight into the mechanism by which S1P(1) agonists function. The selective S1P(1) agonist SEW2871 caused reversible slowing and 'log-jamming' of T cells between filled medullary cords and empty sinuses, whereas motility was unaltered in diffuse cortex. Removal or antagonist competition of SEW2871 permitted recovery of T cell motility in the parenchyma of the medulla and resumption of migration across the stromal endothelial barrier, leading to refilling of sinuses. Our results provide visualization of transendothelial migration of T cells into lymphatic sinuses and suggest that S1P(1) agonists act mainly on endothelial cell S1P(1) receptors to inhibit lymphocyte migration.
Wei
Sindy H
SH
Department of Physiology and Biophysics and Center for Immunology, University of California, Irvine, California 92697-4561, USA.
Rosen
Hugh
H
Matheu
Melanie P
MP
Sanna
M Germana
MG
Wang
Sheng-Kai
SK
Jo
Euijung
E
Wong
Chi-Huey
CH
Parker
Ian
I
Cahalan
Michael D
MD
D000818:Animals; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D008198:Lymph Nodes / Q000166:cytology / Q000502:physiology*; D042601:Lymphatic Vessels / Q000166:cytology / Q000502:physiology*; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010069:Oxadiazoles / Q000494:pharmacology*; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000502:physiology*; D013876:Thiophenes / Q000494:pharmacology*
D008246:Lysophospholipids; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes; C060506:sphingosine 1-phosphate; D013110:Sphingosine