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Enhanced FTY720-Mediated Lymphocyte Homing Requires Gi Signaling and Depends on ₂ and ₇ Integrin¹

Oliver Pabst^*, Heike Herbrand^*, Stefanie Willenzon^*, Tim Worbs^*, Angela Schippers, Werner Müller, Günter Bernhardt^* and Reinhold Förster^2,*

^* Institute of Immunology, Hannover Medical School, Hannover, Germany; and Department of Experimental Immunology, Gesellschaft für Biologische Forschung, Braunschweig, Germany

The immunomodulatory drug FTY720 interferes with sphingosine-1-phosphate (S1P) receptor signaling leading to lymphocyte retention in secondary lymphoid organs and consequently to profound lymphopenia in the peripheral blood. The molecular mechanisms transduced by S1P receptors upon being triggered by its native ligand, S1P, or by FTY720, are largely unknown. In this study we analyze the role of ₂ and ₇ integrin and their ligands ICAM-1, VCAM-1, and MadCAM-1 on lymphocyte homing in the presence of FTY720. We demonstrate that this drug facilitates homing of lymphocytes single-deficient of either ₂ or ₇ integrin but not of ₂-deficient lymphocytes, which in addition were blocked by anti-₇ integrin Abs. Enhanced lymphocyte homing is preceded by increased adherence of integrin-deficient as well as wild-type lymphocytes to high endothelial venules (HEV) in FTY720-treated animals. Elevated adherence to HEV requires intact lymphocyte G_i signaling that cannot be stably imprinted on lymphocytes even after prolonged exposure to FTY720. Thus, FTY720 influences lymphocyte homeostasis not only by suppressing lymphocyte egress from lymph nodes but also by facilitating lymphocyte homing across HEV in an integrin-dependent fashion.

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