Sphingosine 1-phosphate and its type 1 G protein-coupled receptor: trophic support and functional regulation of T lymphocytes.
The lysophospholipid (LPL) growth factors sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) are generated by macrophages, dendritic cells, mast cells, and platelets, which leads to lymph and plasma concentrations of 0.1-1 microM. Distinctive profiles of G protein-coupled receptors (GPCRs) for S1P and LPA are expressed by each type of immune cell and are regulated by cellular activation. At 1-100 nM, S1P signals T cells through their principal S1P(1) GPCRs with consequent protection from apoptosis, enhancement of chemotaxis, and facilitation of optimal regulatory activity of CD4(+)25(+) T cells. At 0.3-3 microM, S1P inhibits T cell chemotaxis and to a lesser extent other functions. These S1P-S1P(1) GPCR signals suppress homing of blood and spleen T cells to secondary lymphoid tissues. S1P(1) GPCR antagonists evoke lymphopenia by permitting blood T cells to enter lymph nodes and blocking S1P(1) GPCR-dependent T cell efflux from lymph nodes. Inversely, there is a decrease in lymphoid tissue traffic of T cells in transgenic mice, which overexpress lymphocyte S1P(1) GPCRs. The immunotherapeutic activity of S1P(1) GPCR antagonists, which limits T cell access to organ grafts and autoimmune antigens, does not reduce other functional capabilities of T cells. LPLs and their GPCRs thus constitute an immunoregulatory system of sufficient prominence for pharmacological targeting in transplantation, autoimmunity, and immunodeficiency.
Goetzl
Edward J
EJ
University of California, 533 Parnassus Ave., Room UB8B, San Francisco, CA 94143-0711. egoetzl@itsa.ucsf.edu
Gräler
Markus H
MH
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008246:Lysophospholipids / Q000276:immunology*; D043562:Receptors, G-Protein-Coupled / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D008246:Lysophospholipids; D043562:Receptors, G-Protein-Coupled; C060506:sphingosine 1-phosphate; D013110:Sphingosine