Regulation of the roles of sphingosine 1-phosphate and its type 1 G protein-coupled receptor in T cell immunity and autoimmunity.

The lipid mediator sphingosine 1-phosphate (S1P) and its type 1 G protein-coupled receptor (S1P1) affect mammalian immunity through alterations in thymocyte emigration, differentiation of T cell subsets, lymphocyte trafficking in lymphoid organs and other tissues, T cell-dendritic cell and T cell-B cell interactions, and cytokine generation. Recent attention to effects of the S1P-S1P1 axis on non-migration functions of lymphocytes includes delineation of a role in terminal differentiation and survival of Th17 effector cells and adaptive Treg cells of the CD4 T cell constellation, and a greater understanding of interactions of the S1P-S1P1 axis with immune cytokines in lymphocyte survival and activities. This breadth of involvement of the S1P-S1P1 axis in immune responses that often are altered in immunological diseases has provided many opportunities for novel therapeutic interventions. A spectrum of pharmacological and immunochemical agents is available that alter immunity by affecting either tissue and fluid concentrations of S1P or levels of expression and signaling activities of S1P1. Such agents have so far been beneficial in the settings of autoimmunity and rejection of transplanted organs, and are likely to become valuable constituents of combined drug programs.