FTY720-enhanced T cell homing is dependent on CCR2, CCR5, CCR7, and CXCR4: evidence for distinct chemokine compartments.
FTY720 stimulates CCR7-driven T cell homing to peripheral lymph nodes (LN) by direct activation of sphingosine 1-phosphate receptors, along with the participation of multidrug transporters, 5-lipoxygenase, and G protein-coupled receptors for chemokines. In this study, we demonstrate that FTY720 also directly stimulates in vitro T cell chemotaxis to CCR2-CCL2, but not to a variety of other chemokines, including CCR5-CCL3/4/5 and CXCR4-CXCL12. FTY720 influences CCR2-CCL2-driven migration through activation of the multidrug transporters, Abcb1 and Abcc1, and through 5-lipoxygenase activity. In vivo administration of FTY720 induces chemokine-dependent migration of T cells in the thymus, peripheral blood, LN, and spleen. The CCR7 and CCR2 chemokine ligands are required for both T cell sequestration in LN and thymic T cell egress following FTY720 administration. Furthermore, FTY720 administration uncovers a requirement for CXCR4 ligands for LN homing, but not for thymic egress, and CCR5 for thymic egress, but not LN homing. FTY720-driven splenic and peripheral blood T cell egress are both independent of CCR2, CCR5, CCR7, or CXCR4. These results indicate that FTY720- and sphingosine 1-phosphate receptor-stimulated T cell migration are dependent on the restricted usage of chemokine receptor-ligand pairs within discrete anatomic compartments.
Yopp
Adam C
AC
Carl C. Icahn Center for Gene Therapy and Molecular Medicine, and. Recanti/Miller Transplantation Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
Fu
Shuang
S
Honig
Shaun M
SM
Randolph
Gwendalyn J
GJ
Ding
Yaozhong
Y
Krieger
Nancy R
NR
Bromberg
Jonathan S
JS
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D011409:Propylene Glycols / Q000494:pharmacology; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000502:physiology*; D054400:Receptors, CCR7; D019718:Receptors, CXCR4 / Q000502:physiology*; D019707:Receptors, Chemokine / Q000187:drug effects / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D018077:Receptors, Leukotriene / Q000502:physiology; D049312:Receptors, Lysophospholipid; D013110:Sphingosine / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*
C515335:Ccr2 protein, mouse; C515371:Ccr7 protein, mouse; D007166:Immunosuppressive Agents; D008024:Ligands; D011409:Propylene Glycols; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; D018077:Receptors, Leukotriene; D049312:Receptors, Lysophospholipid; D001094:Arachidonate 5-Lipoxygenase; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine