Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
NKT cells represent a distinct lineage of T cells that coexpress a conserved alphabeta T cell receptor (TCR) and natural killer (NK) receptors. Although the TCR of NKT cells is characteristically autoreactive to CD1d, a lipid-presenting molecule, endogenous ligands for these cells have not been identified. We show that a lysosomal glycosphingolipid of previously unknown function, isoglobotrihexosylceramide (iGb3), is recognized both by mouse and human NKT cells. Impaired generation of lysosomal iGb3 in mice lacking beta-hexosaminidase b results in severe NKT cell deficiency, suggesting that this lipid also mediates development of NKT cells in the mouse. We suggest that expression of iGb3 in peripheral tissues may be involved in controlling NKT cell responses to infections and malignancy and in autoimmunity.
Sphingosine-1-phosphate (S1P), an important sphingolipid metabolite, regulates diverse cellular processes, including cell survival, growth, and differentiation. Here we show that S1P signaling is critical for neural and vascular development. Sphingosine kinase-null mice exhibited a deficiency of S1P which severely disturbed neurogenesis, including neural tube closure, and angiogenesis and caused embryonic lethality. A dramatic increase in apoptosis and a decrease in mitosis were seen in the developing nervous system. S1P 1 receptor-null mice also showed severe defects in neurogenesis, indicating that the mechanism by which S1P promotes neurogenesis is, in part, signaling from the S1P 1 receptor. Thus, S1P joins a growing list of signaling molecules, such as vascular endothelial growth factor, which regulate the functionally intertwined pathways of angiogenesis and neurogenesis. Our findings also suggest that exploitation of this potent neuronal survival pathway could lead to the development of novel therapeutic approaches for neurological diseases.Sphingosine-1-phosphate (S1P) is a signaling molecule that is crucial for the regulation of several diverse cellular events, including cell survival, growth, differentiation, motility, and calcium mobilization (29). Recently, numerous studies on S1P have demonstrated its importance in the development of the vascular system (1,14,16,18), the heart (15), and immunity (2, 5, 21) by signaling through a family of G protein-coupled receptors designated S1P 1 to S1P 5 . The S1P signaling pathway through S1P receptors induces activation of the protein kinase Akt, phosphatidylinositol 3-kinase, the small GTPase Rac, phospholipase C, and extracellular signal-regulated kinase, leading to cell survival and proliferation (11). In higher plants, S1P also plays an important role in calcium regulation and the control of guard cells (7).Sphingosine kinase (SphK) is an enzyme that catalyzes the phosphorylation of sphingosine to form S1P. Two isoforms of mammalian SphK (SphK1 and SphK2) have been cloned and characterized (13,17). Recent studies revealed that overexpression of SphK2 suppressed cell growth and also markedly enhanced apoptosis in cultured cells (12,19), in sharp contrast to findings for SphK1, which generally promoted cell survival and growth (26,27).Recently, we generated SphK1 knockout mice to study the enzyme's physiological functions (3). The SphK1 Ϫ/Ϫ mice were viable and fertile and lacked any obvious abnormalities, although total SphK activity was substantially, but not completely, reduced. These results raise the possibility that SphK1 and SphK2 might have redundant functions in mice and that SphK2 could compensate for a deficiency in SphK1 activity. To investigate the physiological functions of both isoforms, we generated SphK2 knockout mice, as well as SphK1/SphK2 double-knockout mice. Simultaneous deletion of both enzymes resulted in mice with undetectable levels of S1P. The studies on S1P-deficient mice described herein reveal a novel function for S1P signaling ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.