Although much is known about the migration of T cells from blood to lymph nodes, less is known about the mechanisms regulating the migration of T cells from tissues into lymph nodes through afferent lymphatics. Here we investigated T cell egress from nonlymphoid tissues into afferent lymph in vivo and developed an experimental model to recapitulate this process in vitro. Agonism of sphingosine 1-phosphate receptor 1 inhibited the entry of tissue T cells into afferent lymphatics in homeostatic and inflammatory conditions and caused the arrest, mediated at least partially by interactions of the integrin LFA-1 with its ligand ICAM-1 and of the integrin VLA-4 with its ligand VCAM-1, of polarized T cells at the basal surface of lymphatic but not blood vessel endothelium. Thus, the increased sphingosine 1-phosphate present in inflamed peripheral tissues may induce T cell retention and suppress T cell egress.
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Gene Expression Omnibus
Miyasaka, M. & Tanaka, T. Lymphocyte trafficking across high endothelial venules: dogmas and enigmas. Nat. Rev. Immunol. 4, 360–370 (2004).
Brinkmann, V. et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem. 277, 21453–21457 (2002).
Mandala, S. et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296, 346–349 (2002).
Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004).
Pappu, R. et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 316, 295–298 (2007).
Randolph, G.J., Angeli, V. & Swartz, M.A. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat. Rev. Immunol. 5, 617–628 (2005).
Mackay, C.R., Marston, W.L. & Dudler, L. Naive and memory T cells show distinct pathways of lymphocyte recirculation. J. Exp. Med. 171, 801–817 (1990).
Cose, S., Brammer, C., Khanna, K.M., Masopust, D. & Lefrancois, L. Evidence that a significant number of naive T cells enter non-lymphoid organs as part of a normal migratory pathway. Eur. J. Immunol. 36, 1423–1433 (2006).
Bromley, S.K., Thomas, S.Y. & Luster, A.D. Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. Nat. Immunol. 6, 895–901 (2005).
Debes, G.F. et al. Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Nat. Immunol. 6, 889–894 (2005).
Maly, P. et al. The alpha(1,3)fucosyltransferase Fuc-TVII controls leukocyte trafficking through an essential role in L-, E-, and P-selectin ligand biosynthesis. Cell 86, 643–653 (1996).
Yopp, A.C. et al. Sphingosine 1-phosphate receptors regulate chemokine-driven transendothelial migration of lymph node but not splenic T cells. J. Immunol. 175, 2913–2924 (2005).
Arbiser, J.L. et al. Overexpression of VEGF 121 in immortalized endothelial cells causes conversion to slowly growing angiosarcoma and high level expression of the VEGF receptors VEGFR-1 and VEGFR-2 in vivo. Am. J. Pathol. 156, 1469–1476 (2000).
Graler, M.H. & Goetzl, E.J. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors. FASEB J. 18, 551–553 (2004).
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).
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).
Grubin, C.E., Kovats, S., deRoos, P. & Rudensky, A.Y. Deficient positive selection of CD4 T cells in mice displaying altered repertoires of MHC class II-bound self-peptides. Immunity 7, 197–208 (1997).
Ando, T. et al. Isolation and characterization of a novel mouse lymphatic endothelial cell line: SV-LEC. Lymphat. Res. Biol. 3, 105–115 (2005).
Sironi, M. et al. Generation and characterization of a mouse lymphatic endothelial cell line. Cell Tissue Res. 325, 91–100 (2006).
O'Connell, K.A. & Edidin, M. A mouse lymphoid endothelial cell line immortalized by simian virus 40 binds lymphocytes and retains functional characteristics of normal endothelial cells. J. Immunol. 144, 521–525 (1990).
Kuzmenko, E.S., Djafarzadeh, S., Cakar, Z.P. & Fiedler, K. LDL transcytosis by protein membrane diffusion. Int. J. Biochem. Cell Biol. 36, 519–534 (2004).
Chang, V.W. & Ho, Y. Structural characterization of the mouse Foxf1a gene. Gene 267, 201–211 (2001).
Ohh, M. & Takei, F. Regulation of ICAM-1 mRNA stability by cycloheximide: role of serine/threonine phosphorylation and protein synthesis. J. Cell. Biochem. 59, 202–213 (1995).
Perez, V.L., Henault, L. & Lichtman, A.H. Endothelial antigen presentation: stimulation of previously activated but not naive TCR-transgenic mouse T cells. Cell. Immunol. 189, 31–40 (1998).
Bachmann, C. et al. Targeting mucosal addressin cellular adhesion molecule (MAdCAM)-1 to noninvasively image experimental Crohn's disease. Gastroenterology 130, 8–16 (2006).
Sasaki, M. et al. Transfection of IL-10 expression vectors into endothelial cultures attenuates α4β7-dependent lymphocyte adhesion mediated by MAdCAM-1. BMC Gastroenterol. 3, 3 (2003).
Abello, P.A. & Buchman, T.G. Heat shock-induced cell death in murine microvascular endothelial cells depends on priming with tumor necrosis factor-α or interferon-γ. Shock 2, 320–323 (1994).
Hsu, S.H., Tsou, T.C., Chiu, S.J. & Chao, J.I. Inhibition of α7-nicotinic acetylcholine receptor expression by arsenite in the vascular endothelial cells. Toxicol. Lett. 159, 47–59 (2005).
White, S.J. et al. Targeted gene delivery to vascular tissue in vivo by tropism-modified adeno-associated virus vectors. Circulation 109, 513–519 (2004).
Mueller, S.N. et al. Regulation of homeostatic chemokine expression and cell trafficking during immune responses. Science 317, 670–674 (2007).
Kriehuber, E. et al. Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J. Exp. Med. 194, 797–808 (2001).
Wick, N. et al. Transcriptomal comparison of human dermal lymphatic endothelial cells ex vivo and in vitro. Physiol. Genomics 28, 179–192 (2007).
Amatschek, S. et al. Blood and lymphatic endothelial cell-specific differentiation programs are stringently controlled by the tissue environment. Blood 109, 4777–4785 (2007).
Ebata, N. et al. Immunoelectron microscopic study of PECAM-1 expression on lymphatic endothelium of the human tongue. Tissue Cell 33, 211–218 (2001).
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).
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).
Johnson, L.A. et al. An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. J. Exp. Med. 203, 2763–2777 (2006).
Wei, S.H. 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).
Dejana, E. The transcellular railway: insights into leukocyte diapedesis. Nat. Cell Biol. 8, 105–107 (2006).
Nieminen, M. et al. Vimentin function in lymphocyte adhesion and transcellular migration. Nat. Cell Biol. 8, 156–162 (2006).
Millan, J. et al. Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola- and F-actin-rich domains. Nat. Cell Biol. 8, 113–123 (2006).
Fukui, Y. et al. Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration. Nature 412, 826–831 (2001).
Shulman, Z. et al. DOCK2 regulates chemokine-triggered lateral lymphocyte motility but not transendothelial migration. Blood 108, 2150–2158 (2006).
Shimonaka, M. et al. Rap1 translates chemokine signals to integrin activation, cell polarization, and motility across vascular endothelium under flow. J. Cell Biol. 161, 417–427 (2003).
Katagiri, K., Imamura, M. & Kinashi, T. Spatiotemporal regulation of the kinase Mst1 by binding protein RAPL is critical for lymphocyte polarity and adhesion. Nat. Immunol. 7, 919–928 (2006).
Pabst, O. et al. Enhanced FTY720-mediated lymphocyte homing requires Gαi signaling and depends on α2 and β7 integrin. J. Immunol. 176, 1474–1480 (2006).
Yamaguchi, H. et al. Sphingosine-1-phosphate receptor subtype-specific positive and negative regulation of Rac and haematogenous metastasis of melanoma cells. Biochem. J. 374, 715–722 (2003).
Forster, R. et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99, 23–33 (1999).
Xu, J., Grewal, I.S., Geba, G.P. & Flavell, R.A. Impaired primary T cell responses in L-selectin-deficient mice. J. Exp. Med. 183, 589–598 (1996).
He, X., Dagan, A., Gatt, S. & Schuchman, E.H. Simultaneous quantitative analysis of ceramide and sphingosine in mouse blood by naphthalene-2,3-dicarboxyaldehyde derivatization after hydrolysis with ceramidase. Anal. Biochem. 340, 113–122 (2005).
We thank P. Heeger and R. Jessberger for discussions; V. Brinkmann for reagents; J. Lowe (Cleveland Clinic) for mice lacking fucosyltransferase IV and VII; R. Proia (National Institutes of Health) for S1P1loxP/loxP Lck-Cre mice and littermate controls; and M. Mao, D. Chen, A.M. Ledgerwood, the Mount Sinai Microscopy Core and the Mount Sinai Microarray Facility. Supported by the National Institutes of Health (AI41428 and AI62765 to J.S.B., and DK67381 to S.A.L.), the Emerald Foundation (J.S.B.), the Juvenile Diabetes Research Foundation (1-2005-16 to J.S.B.), Ministerio de Educación y Ciencia, Spain (SAF2007-63579 to J.C.O.) and the Howard Hughes Medical Institute (L.G.L.).
Supplementary Figures 1–5, Table 2 and Methods (PDF 593 kb)
Time-lapse video of untreated T cells migrating across iSVEC4-10. Colored lines represent paths of individual cells over the course of the experiment. (AVI 2499 kb)
Time-lapse video of FTY720-treated T cells migrating across iSVEC4-10. Colored lines represent paths of individual cells over the course of the experiment. (AVI 2448 kb)
Three-dimensional rendering of Z-stack images from untreated T cells migrating across an iSVEC4-10 endothelial layer. T cells (green) were stained with CFSE, endothelial cells (red) stained with PKH26, and slides were mounted with DAPI-containing mounting solution (blue). (AVI 2579 kb)
Three-dimensional rendering of Z-stack images from FTY720-treated T cells migrating across an iSVEC4-10 endothelial layer. T cells (green) were stained with CFSE, endothelial cells (red) were stained with PKH26, and slides were mounted with DAPI-containing mounting solution (blue). (AVI 9888 kb)
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Ledgerwood, L., Lal, G., Zhang, N. et al. The sphingosine 1-phosphate receptor 1 causes tissue retention by inhibiting the entry of peripheral tissue T lymphocytes into afferent lymphatics. Nat Immunol 9, 42–53 (2008) doi:10.1038/ni1534
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