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

Abstract

The lipid mediator sphingosine 1-phosphate (S1P) and its type 1 G protein-coupled receptor (S1P 1 ) 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-S1P 1 axis on nonmigration functions of lymphocytes include 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-S1P 1 axis with immune cytokines in lymphocyte survival and activities. This breadth of involvement of the S1P-S1P 1 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 S1P 1 . 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.

Topical treatment targeting sphingosine‐1‐phosphate and sphingosine lyase abrogates experimental allergic rhinitis in a murine model

“…The underlying mechanism strongly suggests that T‐cell function is altered by FTY720, suppressing Th2 differentiation. Others have suggested that FTY720 supports the induction of Tregs To establish a better insight into how local FTY720 modulates the immune response, we studied its effect on T‐cell proliferation and Th differentiation in vitro and in vivo . T‐cell proliferation was inhibited in vivo in the NALT structures but not in the cervical nodes, due to the topical i.n.…”

Nonimmunologic targets of immunosuppressive agents in podocytes

“…S1P exerts its action by binding to five structurally related G-protein-coupled receptors (S1P1–S1P5 receptors) [52] . Because S1P sequesters lymphocytes and inhibits T-cell chemotaxis and T-cell proliferation [53] , the S1P agonist FTY720 is proposed to treat transplant rejection and autoimmune disease such as multiple sclerosis [54,55] . Besides, FTY720 has a protective effect on ischemia-reperfusion animal models and improved diabetic kidney injury without alterations of T and B cells [56,57] .…”

S1PR1 Is Crucial for Accumulation of Regulatory T Cells in Tumors via STAT3

“…Early studies implicated S1P and S1PR1 in regulating the differentiation of Th2, Treg, and Th17 cells, while limiting Th1 cells (Goetzl et al, 2008). More recent studies have demonstrated that S1PR1 restrains thymic development of Tregs, their peripheral numbers and their suppressive functions (Liu et al, 2009).…”