FTY720 stimulates multidrug transporter- and cysteinyl leukotriene-dependent T cell chemotaxis to lymph nodes.
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.
Honig
Shaun M
SM
Carl C. Icahn Center For Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Fu
Shuang
S
Mao
Xia
X
Yopp
Adam
A
Gunn
Michael D
MD
Randolph
Gwendalyn J
GJ
Bromberg
Jonathan S
JS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology; D054415:Chemokine CCL19; D019742:Chemokines, CC / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003545:Cysteine / Q000378:metabolism / Q000502:physiology*; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015289:Leukotrienes / Q000378:metabolism / Q000502:physiology*; D008198:Lymph Nodes / Q000276:immunology*; D008246:Lysophospholipids; D051379:Mice; D008810:Mice, Inbred C57BL; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D010766:Phosphorylation; D011409:Propylene Glycols / Q000494:pharmacology; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D013110:Sphingosine / Q000031:analogs & derivatives*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001094:Arachidonate 5-Lipoxygenase; D054415:Chemokine CCL19; D019742:Chemokines, CC; D003545:Cysteine; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents; D015289:Leukotrienes; D008246:Lysophospholipids; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011409:Propylene Glycols; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D013110:Sphingosine; C515461:Ccl19 protein, mouse; C112381:cysteinyl-leukotriene; C060506:sphingosine 1-phosphate; C421109:multidrug resistance-associated protein 1