Physiological sphingosine 1-phosphate requirement for optimal activity of mouse CD4+ 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 S1P1 G protein-coupled receptor (R). Mouse CD4+25+ regulatory T cells now are shown to express the same pattern of S1P1 > S1P4 >>other S1P Rs as other CD4 T cells. CD4+25+ T cell suppression of 3H-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.