Sphingosine-1-phosphate receptor agonism impairs the efficiency of the local immune response by altering trafficking of naive and antigen-activated CD4+ T cells.
FTY720 (2-amino-[2-(4-octylphenyl) ethyl]-1,3-propanediol hydrochloride) is an immunosuppressive agent that inhibits allograft rejection. We recently demonstrated that FTY-phosphate, the active metabolite of FTY720, acts as a full agonist for sphingosine-1-phosphate (S1P) receptors. Furthermore, activation of S1P receptors with their natural ligand, S1P, as well as pharmacological ligands leads to lymphopenia, probably due to sequestration of lymphocytes in secondary lymphoid organs. In the present study we used a local Ag-challenged mouse model to examine the effects of FTY720 on T cell activation in the draining lymph node (DLN) and on the release of activated T cells to the peripheral blood compartment. We showed that the number of Ag-activated CD4(+) T cells in the DLN after injection of Ag and CFA into a footpad was dramatically reduced after FTY720 treatment. However, T cell proliferation, both in vitro and in vivo, was not impaired by FTY720. Our results suggest that the reduced efficiency of T cell responses in the DLN in response to a local Ag is probably due to a defective recirculation of naive T cells caused by FTY720 treatment. Furthermore, we found that the numbers of naive and Ag-activated CD4(+) T cells in the peripheral blood of Ag-challenged mice were equally reduced with FTY720 treatment, suggesting that both T cell subsets are sequestered in the DLNs. Thus, FTY720 induces immunosuppression through inhibition of both the recirculation of naive T cells and the release of Ag-activated T cells from the DLN to lymph and to the blood compartment.
Xie
Jenny H
JH
Department of Pharmacology, Merck Research Laboratories, Rahway NJ 07065, USA. jenny_xie@merck.com
Nomura
Naomi
N
Koprak
Sam L
SL
Quackenbush
Elizabeth J
EJ
Forrest
Michael J
MJ
Rosen
Hugh
H
D000818:Animals; D000941:Antigens / Q000008:administration & dosage / Q000494:pharmacology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D005452:Fluoresceins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D007279:Injections, Subcutaneous; D007399:Interphase / Q000187:drug effects / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000494:pharmacology*; D011409:Propylene Glycols / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000819:agonists*; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D013110:Sphingosine / Q000378:metabolism*; D013388:Succinimides / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology
C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D000941:Antigens; D018984:Epitopes, T-Lymphocyte; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D013388:Succinimides; D010047:Ovalbumin; D001973:Bromodeoxyuridine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine