The Sphingosine 1-Phosphate Receptor Agonist FTY720 Differentially Affects the Sequestration of CD4+/CD25+ T-Regulatory Cells and Enhances Their Functional Activity

Abstract

The sphingosine 1-phosphate (S1P) receptor agonist FTY720 is well known for its immunomodulatory activity, sequestering lymphocytes from blood and spleen into secondary lymphoid organs and thereby preventing their migration to sites of inflammation. Because inflammation is critically dependent on a balance between Ag-specific Th/effector cells and T-regulatory cells, we investigated the effect of FTY720 on T-regulatory cell trafficking and functional activity. An increased number of CD4+/CD25+ T cells was found in blood and spleens of FTY720-treated mice, and transfer of these cells resulted in a significantly more pronounced accumulation in spleens but not lymph nodes after treatment, suggesting that this compound differentially affects the homing properties of T-regulatory cells compared with other T cell subsets. Indeed, CD4+/CD25+ T cells express lower levels of S1P1 and S1P4 receptors and demonstrate a reduced chemotactic response to S1P. Moreover, analysis of the functional response of FTY720-treated CD4+/CD25+ T cells revealed an increased suppressive activity in an in vitro Ag-specific proliferation assay. This correlated with enhanced function in vivo, with T-regulatory cells obtained from FTY720-treated mice being able to suppress OVA-induced airway inflammation. Thus, FTY720 differentially affects the sequestration of T-regulatory cells and importantly, increases the functional activity of T-regulatory cells, suggesting that it may have disease-modifying potential in inflammatory disorders.

FTY720 Ameliorates Th1-Mediated Colitis in Mice by Directly Affecting the Functional Activity of CD4+CD25+ Regulatory T Cells

“…The fact that FTY720 did not change the expression of GITR as well as the point that GITR seems to be constitutively expressed on CD4 ϩ CD25 ϩ Treg might again underline our hypothesis that FTY720 directly alters the functional activity of CD4 ϩ CD25 ϩ Treg. Still, we consider that this direct impact on CD4 ϩ CD25 ϩ Treg function might additionally be facilitated by a differently regulated sequestration of CD4 ϩ CD25 ϩ Treg vs inflammatory effector T cells resulting in a higher ratio of Treg/effector cells in blood and inflammatory sites (25,26).…”

“…Recently, S1P was demonstrated to be required for optimal suppression of effector T cell activities by Treg (25). Additionally another group showed that the S1P mimetic FTY720 differentially affected the recirculation of Treg vs memory effector T cells (26). However, in the latter investigation it was also considered that modulation of migration might not be the end of the story regarding its impact on Treg.…”

“…However, in the latter investigation it was also considered that modulation of migration might not be the end of the story regarding its impact on Treg. Indeed, FTY720 may additionally alter the functional activity of Treg directly or via "tolerogenic" DC (25)(26)(27)(28)(29)(30). Thus, a more complex mode of action may be supported by the fact that the affinity profile of FTY720-P on S1PRs is not identical to S1P.…”

Sphingosine-1-Phosphate Reduces CD4+ T-Cell Activation in Type 1 Diabetes Through Regulation of Hypoxia-Inducible Factor Short Isoform I.1 and CD69

“…Nofer et al (8) have recently reported that FTY720 reduces atherosclerosis in LDL receptor-deficient mice. Other studies have shown the importance of S1P and the S1P1 receptor in modulating T-cell proliferation and homing to lymph nodes (9,10). Furthermore, S1P has recently been shown to regulate lymphocyte egress from peripheral lymph nodes through interaction with the adaptor protein DOCK2 (11).…”

The sphingosine-1-phosphate receptor agonist FTY720 and its phosphorylated form affect the function of CD4+CD25+ T cells in vitro

“…It is known that S1PR is expressed on Treg cells and influences Treg development, maintenance, and suppressor function (22). In addition, it has been reported that S1P1 can block the differentiation of thymic Treg precursors and function of mature Treg cells and affect Treg cell-mediated immune tolerance (17).…”