FoxP3+ T cells (or commonly called Tregs) are made in both the thymus and the periphery and can assume a naıve or memory phenotype in terms of trafficking ability. 1 FoxP3+ T cells can suppress diverse immune cells, such as T cells (CD4, CD8 and natural killer T cells), B cells, dendritic cells, macrophages, mast cells and natural killer cells. FoxP3+ T cells dampen overactive immune responses and promote immune tolerance. 2 Defective production of FoxP3+ regulatory T cells causes lethal autoimmune diseases in multiple organs in mice and humans. On account of their potent immune suppressive function, FoxP3+ T cells can be exploited by pathogens and cancers as a mechanism of immune evasion. Similarly, uncontrolled production or activity of FoxP3+ T cells could lead to fatal immunodeficiency. Therefore, generation of thymic and peripheral FoxP3+ T cells should be controlled at appropriate levels to promote a balance between immunity and tolerance. Many factors have been identified that regulate the generation and function of FoxP3+ T cells. 2–4 These include the specificity and affinity of T-cell receptors, cytokines (interleukin (IL-2) and transforming growth factor-β1), co-stimulatory receptors (CTLA4, CD28, OX40 and GITR) and TLR signals. Many of these signals would eventually alter the status of methylation and acetylation at the FoxP3 promoter and associated regulatory sequences for the induction or suppression of expression of the FoxP3 gene. A recent report in Nature Immunology identified another factor—sphingosine 1-phosphate (S1P)—that has an important role in restraining the development and function of FoxP3+ T cells. 5

Sphingosine 1-phosphate is made from sphingosine by sphingosine kinases and can be degraded by sphingosine lyase. 6 S1P has five 7-transmembrane G-protein-coupled receptors from S1P1 through S1P5. S1P1 is the major receptor that mediates the effect of S1P in immune cells. Erythrocytes and platelets in the blood are the major producers of S1P, and S1P is present in the blood plasma at the highest concentration (B3000 nM). The concentration of S1P in the lymph is lower but is still relatively high (B500 nM). Compared with the blood and lymph, thymus and secondary lymphoid tissues have very low levels of S1P most likely due to active degradation of S1P by S1P lyase. 7 Thus, there is an increasing gradient of S1P in the emigration pathway for lymphocytes (organ–lymph–blood)(Figure 1a). It is thought that S1P induces egress of lymphocytes because it acts as a chemoattractant for S1P1-expressing immune cells and modulates the responsiveness of emigrating cells to other chemoattractants. In addition, S1P may act on endothelial cells and condition them for transendothelial lymphocyte emigration. 8 The functions of S1P and their receptors became well known because of the discovery of FTY720 (a sphingosine analog derived from a fungal metabolite). FTY720 becomes active after phosphorylation in vivo and blocks the function of its natural counterpart, S1P, most likely through internalization of S1P1. 9 FTY720 induces the depletion of circulating lymphocytes by suppressing the egress of lymphocytes from lymphoid tissues and is currently under clinical trials as a new form of immunosuppressant. Similarly, S1P1 null mice have problems with lymphocyte egress from the thymus and lymph nodes. 10, 11 An initial connection between S1P and FoxP3+ T cells was made by Sawicka et al., 12