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Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses

Abstract

Sphingosine 1-phosphate type 1 (S1P1) 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 S1P1 receptors on lymphocytes; a second hypothesis proposes instead that S1P1 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 S1P1 agonists or antagonists has provided insight into the mechanism by which S1P1 agonists function. The selective S1P1 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 S1P1 agonists act mainly on endothelial cell S1P1 receptors to inhibit lymphocyte migration.

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Figure 1: Delineation of structures in control or SEW2871-treated lymph nodes by a fluorescent lectin that overlaps with LYVE-1 staining.
Figure 2: Motility and transendothelial migration of T cells are inhibited by SEW2781 but rapidly recover after drug washout.
Figure 3: Selective and reversible inhibition of T cell motility in the medulla.
Figure 4: Directionality of T cell movement.
Figure 5: Imaging of lymphocyte migration across the stromal barrier.
Figure 6: Rapid reversal of SEW2871 action by superfusion with the selective S1P1 antagonist W123.

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Acknowledgements

We thank O. Safrina for some T cell isolation procedures; L. Forrest for guidance on animal handling; M. Peterson for lymph node immunohistology; X. Duong-Polk for the GTPγS assays; W. Cheng for VPC23019; and D. Jackson (University of Oxford, Oxford, UK) for the gift of LYVE-1. Supported by the National Institutes of Health (GM-41514 to M.D.C., GM-48071 to I.P., and AI-55509 and MH074404-01 to H.R.).

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Correspondence to Hugh Rosen or Michael D Cahalan.

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Supplementary information

Supplementary Fig. 1

Schematic diagram showing orientation of the lymph node, with major anatomical specializations, during two-photon imaging of the medulla. (PDF 661 kb)

Supplementary Fig. 2

Schematic diagram illustrates the mechanism by which S1P1 agonists may regulate lymphocyte egress from the node through closing of portals in the endothelial barrier. (PDF 755 kb)

Supplementary Fig. 3

Characterization of competitive S1P1 receptor antagonist W123. (PDF 142 kb)

Supplementary Video 1

3D reconstruction of lymphatic sinuses and T cell localization. (MOV 4477 kb)

Supplementary Video 2

Recovery of T cell motility and transendothelial migration during washout of SEW2871. (MOV 2378 kb)

Supplementary Video 3

Constitutive T cell motility and transendothelial migration in the absence of SEW2871. (MOV 2344 kb)

Supplementary Video 4

SEW2871 has no effect on motility in the T cell zone. (MOV 2377 kb)

Supplementary Video 5

Passive, unidirectional flow of T cells within the medullary sinus. (MOV 1203 kb)

Supplementary Video 6

Example of a single T cell traversing the sinus endothelial barrier during washout of SEW2871. (MOV 880 kb)

Supplementary Video 7

Bi-directional trafficking of an individual T cell across the sinus wall in a control axillary lymph node. (MOV 1840 kb)

Supplementary Video 8

T cells cross the sinus endothelial barrier through stromal 'portals'. (MOV 3574 kb)

Supplementary Video 9

W123 reverses the actions of SEW2871 by restoring T cell motility and transendothelial migration. (MOV 2853 kb)

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Wei, S., Rosen, H., Matheu, M. et al. Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses. Nat Immunol 6, 1228–1235 (2005). https://doi.org/10.1038/ni1269

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