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 μM. 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 S1P1 GPCRs with consequent protection from apoptosis, enhancement of chemotaxis, and facilitation of optimal regulatory activity of CD4+25+ T cells. At 0.3–3 μM, S1P inhibits T cell chemotaxis and to a lesser extent other functions. These S1P–S1P1 GPCR signals suppress homing of blood and spleen T cells to secondary lymphoid tissues. S1P1 GPCR antagonists evoke lymphopenia by permitting blood T cells to enter lymph nodes and blocking S1P1 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 S1P1 GPCRs. The immunotherapeutic activity of S1P1 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.