title: Sphingosine 1-phosphate receptor agonist FTY720-phosphate causes marginal zone B cell displacement.
abstract: FTY720 is an immunosuppressive agent that modulates lymphocyte trafficking. It is phosphorylated in vivo to FTY720-phosphate (FTY-P) and binds to a family of G protein-coupled receptors recognizing sphingosine 1-phosphate (S1P) as the natural ligand. It has previously been reported that FTY-P blocks egress of lymphocytes from the thymus and lymph nodes, resulting in peripheral blood lymphopenia. We now report that FTY-P also causes displacement of marginal zone (MZ) B cells to the splenic follicles, an effect that is similar to that observed after in vivo administration of lipopolysaccharide. This effect is specific to B cells in the MZ, as treatment with FTY-P does not cause redistribution of the resident macrophage population. A small but statistically significant decrease in the expression of beta1 integrin on MZ B cells was observed with FTY-P treatment. The redistribution of MZ B cells from the MZ sinuses does not abolish the ability of these cells to respond to the T-independent antigen, trinitrophenol-Ficoll. It has been proposed that the displacement of MZ B cells to the follicles is an indication of cell activation. Consistent with this, FTY-P caused an increase in percentage of MZ B cells expressing activation markers CD9, CD1d, and CD24. These results suggest that S1P receptors on MZ B cells are responsible for their mobilization to follicles.
authors.affiliation: Department of Immunology, Merck Research Laboratories, 126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ 07065, USA. Kalpit_vora@merck.com
authors.forename: Kalpit A
authors.initials: KA
authors.lastname: Vora
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nichols
authors.forename: Gene
authors.initials: G
authors.lastname: Porter
authors.forename: Yan
authors.initials: Y
authors.lastname: Cui
authors.forename: Carol Ann
authors.initials: CA
authors.lastname: Keohane
authors.forename: Richard
authors.initials: R
authors.lastname: Hajdu
authors.forename: Jeffery
authors.initials: J
authors.lastname: Hale
authors.forename: William
authors.initials: W
authors.lastname: Neway
authors.forename: Dennis
authors.initials: D
authors.lastname: Zaller
authors.forename: Suzanne
authors.initials: S
authors.lastname: Mandala
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D005260:Female; D000068876:Fingolimod Hydrochloride; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D018858:Germinal Center / Q000166:cytology / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology; D008221:Lymphoid Tissue / Q000166:cytology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D011409:Propylene Glycols / Q000008:administration & dosage*; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives
chemical_list: D015703:Antigens, CD; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine