Physiological sphingosine 1‐phosphate requirement for optimal activity of mouse CD4 + 25 + regulatory T Cells

Sphingosine 1‐phosphate (S1P) evokes T cell chemotaxis at 1–100 nM and inhibits chemotaxis to chemokines at 300 nM–1 uM through their predominant S1P 1 G protein‐coupled receptor (R). Mouse CD4+25+ regulatory T cells now are shown to express the same pattern of S1P 1 > S1P 4 >>other S1P Rs as other CD4 T cells. CD4 + 25 + T cell suppression of 3 H‐thymidine uptake and IL‐2 generation by CD4 + 25 − T cells stimulated with anti‐T cell receptor antibodies without S1P was enhanced significantly by S1P at normal blood and lymph concentrations. These levels of S1P also enhanced IL‐10 generation by CD4 + 25 + T cells by up to threefold compared with that without S1P but decreased IL‐10 from CD4 + 25 − T cells. That IL‐10 from CD4 + 25 + T cells incubated with S1P mediates suppressive activity was demonstrated by prevention with neutralizing anti‐IL‐10 or anti‐IL‐10 receptor antibodies. Extracellular fluid S1P thus is required for optimal activity of CD4 + 25 + T cells.