Enhanced FTY720-mediated lymphocyte homing requires G alpha i signaling and depends on beta 2 and beta 7 integrin.
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 beta2 and beta7 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 beta2 or beta7 integrin but not of beta2-deficient lymphocytes, which in addition were blocked by anti-beta7 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 Galphai 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.
Pabst
Oliver
O
Institute of Immunology, Hannover Medical School, Hannover, Germany.
Herbrand
Heike
H
Willenzon
Stefanie
S
Worbs
Tim
T
Schippers
Angela
A
Müller
Werner
W
Bernhardt
Günter
G
Förster
Reinhold
R
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D018821:CD18 Antigens / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D004729:Endothelium, Lymphatic / Q000098:blood supply / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D000068876:Fingolimod Hydrochloride; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology; D016219:Immunotherapy, Adoptive; D039641:Integrin beta Chains / Q000235:genetics / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects; D017710:Lymphocyte Transfusion / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009088:Mucoproteins; D011409:Propylene Glycols / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D000276:Adjuvants, Immunologic; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D039641:Integrin beta Chains; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D011409:Propylene Glycols; D019010:Vascular Cell Adhesion Molecule-1; C091368:integrin beta7; D018799:Intercellular Adhesion Molecule-1; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine