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

ABSTRACTSphingosine 1‐phosphate (S1P) has diverse effects on T cells that are mediated by the predominant S1P1 and S1P4 G protein‐coupled receptors (GPCRs). S1P4 is expressed principally by leukocytes, but little is known of its T cell effects in immunity. Two approaches were used to investigate S1P4 signals in T cells. First, S1P4 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 S1P4 GPCRs as the only functionally relevant S1P receptor. Unlike S1P1, S1P4 failed to transduce chemotactic responses of any of the S1P4‐only T cells to S1P or the phyto‐S1P ligand selective for S1P4, or to suppress their chemotactic responses to chemokines. The S1P‐S1P4 axis significantly inhibited T cell proliferation in each of the S1P4‐only T cells activated by anti‐CD3 and anti‐CD28 MoAbs. Secretion of IL‐4 by S1P4‐D10G4.1 cells, IL‐2 by S1P4‐EL4.IL‐2, and IFN‐γ by FTY720‐treated CD4 T cells were significantly inhibited by S1P. In contrast, S1P enhanced secretion of IL‐10 by stimulated S1P4‐D10G4.1 T cells. Thus, S1P4 mediates immunosuppressive effects of S1P by inhibiting proliferation and secretion of effector cytokines, while enhancing secretion of the suppressive cytokine IL‐10.