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. 2003 Mar;111(5):627-37.
doi: 10.1172/JCI16200.

FTY720 Stimulates Multidrug Transporter- And Cysteinyl Leukotriene-Dependent T Cell Chemotaxis to Lymph Nodes

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Free PMC article

FTY720 Stimulates Multidrug Transporter- And Cysteinyl Leukotriene-Dependent T Cell Chemotaxis to Lymph Nodes

Shaun M Honig et al. J Clin Invest. .
Free PMC article

Abstract

FTY720 is a sphingosine-derived immunosuppressant. Phosphorylated FTY720 promotes T cell homing from spleen and peripheral blood to LNs by acting as an agonist for sphingosine-1-phosphate (S1P) receptors. Here we demonstrate that FTY720 enhances the activity of the sphingosine transporter Abcb1 (Mdr1) and the leukotriene C(4) transporter Abcc1 (Mrp1). Both transporters must be active for FTY720-mediated T cell migration and LN homing. Migration and homing driven by FTY720, phosphorylated FTY720, or S1P also require 5-lipoxygenase-mediated synthesis of cysteinyl leukotrienes and their efflux from the cell. FTY720-mediated LN homing events further downstream are dependent on CCL19, CCL21, VLA-4alpha, and CD44. Use of T cells deficient in 5-lipoxygenase, Abcb1, and Abcc1, and comparison of the effects of FTY720 with those of S1P, suggest a model of sequential engagement of Abcb1, SP1 receptors, 5-lipoxygenase, and Abcc1 to enhance T cell migration and homing.

Figures

Figure 1
Figure 1
FTY720 enhances efflux activity of the Abcb1 and Abcc1 transporters. (ad) Abcb1 efflux activity (a and c) and Abcc1 efflux activity (b and d) in wild-type C57BL/6 T cells. (e and f) Abcb1 (e) and Abcc1 (f) efflux activity in Abcc1–/– T cells. (g and h) Abcb1 (g) and Abcc1 (h) efflux activity in Abcb1–/– T cells.
Figure 2
Figure 2
FTY720 and S1P cause Abcc1- and Abcb1-dependent migration to CCL19 and CCL21. In vitro chemotactic response of T cells from wild-type mice to CCL19 or CCL21 is shown. FTY720, S1P, PSC833, and MK571 were added as indicated.
Figure 3
Figure 3
FTY720 causes Abcc1- and Abcb1-dependent LN homing in vivo. In vivo migration from peripheral blood and spleen to LNs in response to FTY720 in fvb wild type (a), Abcc1–/– (b), and Abcb1–/– (c). Total T cells are indicated.
Figure 4
Figure 4
FTY720-mediated migration and S1P-mediated migration are dependent on cysLTs. (a and b) In vitro chemotactic response of T cells from wild-type or 5-LO–/– mice to CCL19 and FTY720 plus the 5-LO blocker AA-861 or the 12-LO blocker CDC. (c and d) Chemotactic response of T cells from 5-LO–/– and wild-type mice to CCL19 and S1P plus AA-861 or CDC. (e) Chemotactic response of T cells treated with CCL19 and with FTY720, FTY720 plus AA-861, or FTY720 plus AA-861 plus LTD4. (f) In vitro chemotactic response of T cells treated with FTY720 or FTY720 supernatant. (g) Chemotactic response of T cells treated with supernatants from FTY720, FTY720 plus AA-861, or FTY720 plus CDC-treated T cells. (h and i) Chemotactic response of fvb wild-type or fvb Abcc1–/– T cells treated with CCL19 and FTY720 or supernatant from FTY720-treated T cells. (j) In vivo migration from peripheral blood and spleen to LNs in response to FTY720 in 5-LO–/– mice. Total T cells are indicated.
Figure 5
Figure 5
FTY720 enhances migration to CCL19 and CCL21 but not to other chemokines. FTY720 causes T cell LN homing in vivo in C57BL/6 wild-type (a) and CX3CR1–/– (c) but not plt (b) mice.
Figure 6
Figure 6
FTY720 causes CD44- and VLA-4α–dependent T cell LN homing in vivo. C57BL/6 wild-type (a), L-selectin–/– (b), and FucTVII–/– (c) mice and mice treated with anti-CD62L (d), anti-CD44 (e), or anti–VLA-4α (f) mAb received either vehicle or FTY720.
Figure 7
Figure 7
FTY720 causes multidrug transporter–independent apoptosis. Percent apoptosis after the indicated treatments with FTY720 plus multidrug transporter blockers is shown.
Figure 8
Figure 8
Model for interactions among transporters and enzymes for autocrine or paracrine signaling in T cells leading to chemotaxis.

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