Type 4 sphingosine 1-phosphate G protein-coupled receptor (S1P4) transduces S1P effects on T cell proliferation and cytokine secretion without signaling migration

Sphingosine 1-phosphate (S1P) has diverse effects on T cells that are mediated by the predominant S1P(1) and S1P(4) G protein-coupled receptors (GPCRs). S1P(4) is expressed principally by leukocytes, but little is known of its T cell effects in immunity. Two approaches were used to investigate S1P(4) signals in T cells. First, S1P(4) was introduced into D10G4.1 mouse Th2 cells and EL4. IL-2 mouse T cells lacking endogenous S1P GPCRs. Second, mouse splenic CD4 T cells were treated with FTY720 to suppress S1P1 and leave S1P(4) GPCRs as the only functionally relevant S1P receptor. Unlike S1P(1), S1P(4) failed to transduce chemotactic responses of any of the S1P(4)- only T cells to S1P or the phyto-S1P ligand selective for S1P(4), or to suppress their chemotactic responses to chemokines. The S1P-S1P(4) axis significantly inhibited T cell proliferation in each of the S1P(4)- only T cells activated by anti-CD3 and anti-CD28 MoAbs. Secretion of IL-4 by S1P(4)-D10G4.1 cells, IL-2 by S1P(4)-EL4. IL-2, and IFN-gamma by FTY720-treated CD4 T cells were significantly inhibited by S1P. In contrast, S1P enhanced secretion of IL- 10 by stimulated S1P(4)- D10G4.1 T cells. Thus, S1P(4) mediates immunosuppressive effects of S1P by inhibiting proliferation and secretion of effector cytokines, while enhancing secretion of the suppressive cytokine IL-10.