Type 1 sphingosine 1‐phosphate G protein‐coupled receptor signaling of lymphocyte functions requires sulfation of its extracellular amino‐terminal tyrosines

The type 1 sphingosine 1‐phosphate (S1P) G protein‐coupled receptor (S1P 1 ) transduces signals from S1P that mediate thymocyte emigration, T cell transmigration of lymph nodes, and T cell chemotaxis in tissues. Alterations in expression of functional S1P 1 receptors by lymphocytes are the major mechanisms controlling their responses to S1P and were thought to be solely a consequence of the balance between surface down‐regulation and insertion. However, results now show that lack of sulfation of tyrosines 19 and 22 of the extracellular N terminus of S1P 1 diminishes high‐affinity S1P binding and decreases S1P signaling of T cell migration and other functions. Non‐sulfatable mutant (Y19,22F)S1P 1 endows T cells with lower‐affinity binding of [ 32 P]S1P than wild‐type S1P 1 and transduces lesser effects of S1P on chemotaxis, chemokine‐elicited chemotaxis, and T cell receptor‐mediated proliferation and cytokine generation. Inhibition of S1P 1 tyrosine sulfation or sulfatase removal of S1P 1 sulfate in mouse CD4 T cells suppresses immune functional effects of S1P. Tyrosine sulfation of S1P 1 may be a major controller of S1P effects on T cell traffic.