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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References
Brinkmann, V. FTY720: mechanism of action and potential benefit in organ transplantation. Yonsei Med. J. 45, 991–997 (2004).
Mandala, S. et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296, 346–349 (2002).
Sanna, M.G. et al. Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J. Biol. Chem. 279, 13839–13848 (2004).
Rosen, H., Sanna, G. & Alfonso, C. Egress: a receptor-regulated step in lymphocyte trafficking. Immunol. Rev. 195, 160–177 (2003).
Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004).
Allende, M.L., Dreier, J.L., Mandala, S. & Proia, R.L. Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J. Biol. Chem. 279, 15396–15401 (2004).
Cinamon, G. et al. Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone. Nat. Immunol. 5, 713–720 (2004).
Miller, M.J., Wei, S.H., Cahalan, M.D. & Parker, I. Autonomous T cell trafficking examined in vivo with intravital two-photon microscopy. Proc. Natl. Acad. Sci. USA 100, 2604–2609 (2003).
Miller, M.J., Wei, S.H., Parker, I. & Cahalan, M.D. Two-photon imaging of lymphocyte motility and antigen response in intact lymph node. Science 296, 1869–1873 (2002).
Jo, E. et al. S1P1-selective in vivo-active agonist from high throughput screening: Off-the-shelf chemical probes of receptor interactions, signaling and fate. Chem. Biol. 12, 703–715 (2005).
Davis, M.D., Clemens, J.J., Macdonald, T.L. & Lynch, K.R. Sphingosine 1-phosphate analogs as receptor antagonists. J. Biol. Chem. 280, 9833–9841 (2005).
Halin, C. et al. The S1P-analog FTY720 differentially modulates T cell homing via HEV: T cell-expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer's patches. Blood 106, 1314–1322 (2005).
Cyster, J.G. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu. Rev. Immunol. 23, 127–159 (2005).
Graler, M.H. & Goetzl, E.J. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors. FASEB J. 18, 551–553 (2004).
Rosen, H., Alfonso, C., Surh, C.D. & McHeyzer-Williams, M.G. Rapid induction of medullary thymocyte phenotypic maturation and egress inhibition by nanomolar sphingosine 1-phosphate receptor agonist. Proc. Natl. Acad. Sci. USA 100, 10907–10912 (2003).
Forrest, M. et al. Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes. J. Pharmacol. Exp. Ther. 309, 758–768 (2004).
Brinkmann, V., Cyster, J.G. & Hla, T. FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am. J. Transplant. 4, 1019–1025 (2004).
Sanchez, T. et al. Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability. J. Biol. Chem. 278, 47281–47290 (2003).
Peng, X. et al. Protective effects of sphingosine 1-phosphate in murine endotoxin-induced inflammatory lung injury. Am. J. Respir. Crit. Care Med. 169, 1245–1251 (2004).
Gon, Y. et al. S1P3 receptor-induced loss of epithelial tight junctions compromises lung barrier integrity. Proc. Natl. Acad. Sci. USA 102, 9270–9275 (2005).
Rosen, H. & Goetzl, E.J. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat. Rev. Immunol. 5, 560–570 (2005).
Lo, C.G., Xu, Y., Proia, R.L. & Cyster, J.G. Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit. J. Exp. Med. 201, 291–301 (2005).
Yagi, H. et al. Immunosuppressant FTY720 inhibits thymocyte emigration. Eur. J. Immunol. 30, 1435–1444 (2000).
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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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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DOI: https://doi.org/10.1038/ni1269
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