Immunosuppressant FTY720 inhibits thymocyte emigration

Abstract

One major role of the thymus is to provide the peripheral immune system with mature T cells, but the mechanisms involving the cellular export are not fully understood. In this study, we examined the ability of a novel immunosuppressive reagent, FTY720, to inhibit T cell export from the thymus. Daily administration of FTY720 at a dose of 1 mg / kg resulted in a marked decrease in the number of peripheral blood T lymphocytes. In the thymus, long-term daily administration of FTY720 caused a three- to fourfold increase in the proportion of mature medullary thymocytes (CD4(+)CD8(-) and CD4(-)CD8(+)) as well as a slight decrease in the double-positive cell (CD4(+)CD8(+)) ratio. Phenotypic analysis (TCRalpha beta, H-2K(d), CD44, CD69 and CD24) revealed that these increased subsets represent possible peripheral recent thymic emigrants. High level expression of L-selectin by these subsets further suggests that they were prevented from leaving the thymus. By intrathymic labeling with fluorescein isothiocyanate, only one fourth of labeled cells could be detected in the lymph nodes and in the spleen of FTY720-treated mice compared to saline-treated control mice. Taken together, these results suggest that the immunosuppressive action of FTY720, at least in part, could be due to its inhibitory effect on T cell emigration from the thymus to the periphery.

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“…FTY 720 does not impair lymphocyte function, including T-cell activation, but induces the sequestration of circulating mature lymphocytes into the secondary lymphoid tissues and decreases T-cell infiltration into grafted organs [19]. It also inhibits the migration of naïve T cells from thymus into the blood, resulting in a declining supply of naïve T cells to the grafts [48].…”

Expression of the Sphingosine 1-Phosphate Receptor, S1P1, on T-cells Controls Thymic Emigration

“…Intrathymic Labeling of Thymocytes-Thymocytes were labeled as previously described (25,28). Briefly, mice were anesthetized with Avertin (Sigma).…”

“…FTY720, a sphingosine analogue, is phosphorylated by sphingosine kinase type I and more efficiently by sphingosine kinase type II (19 -21) and functions as an agonist ligand for S1P 1 , S1P 3 , S1P 4 , and S1P 5 receptors (19,22). FTY720 causes lymphopenia through sequestration of circulating lymphocytes within lymph nodes and Peyer's patches (19,(22)(23)(24) and also blocks the egress of T-cells from the thymus (25,26). However, it is not known at which S1P receptor and cell type FTY720 exerts its effects.…”

Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720

“…FTY720 is a sphingosine analogue that, when phosphorylated, functions as an agonist for four of the five S1P receptors (S1P 1 , S1P 3 , S1P 4 , and S1P 5 but not S1P 2 ) (13,27). FTY720-P causes lymphopenia through sequestration of circulating lymphocytes within lymph nodes and Peyer's patches and also blocks the exit of T-cells from thymus (13,(27)(28)(29)(30). Deletion of the S1P 1 receptor on thymocytes blocks egress of mature T-cells from thymus and, thus, their presence in the periphery (11,12).…”