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Prepublished online as a Blood First Edition Paper on February 13, 2003; DOI 10.1182/blood-2002-09-2962.
Submitted September 27, 2002
Accepted February 5, 2003
Sphingosine 1-phosphate is a novel inhibitor of T cell proliferation
Yixin Jin, Eirunn Knudsen, Ling Wang, Yenan Bryceson, Basam Damaj, Sandra Gessani, and Azzam A Maghazachi*
University of Oslo, Oslo, Norway
Lab. of Immunogenetics, NIH, Rockville, MD, USA
Bio-Quant, San Diego, CA, USA
Virology, Inst. Sup. Di Sanita, Rome, Italy
* Corresponding author; email: azzam.maghazachi{at}basalmed.uio.no.
Sphingosine 1-phosphate (S1P) is a pleiotropic lysosphingophospholipid stored and secreted by platelets. Utilizing RT-PCR and flow cytometric analyses, we determined the expression of S1P receptors (S1P1, S1P3, S1P4 and S1P5) in peripheral blood T cells. T cells were induced to proliferate in the presence of PMA plus ionomycin, anti-CD3 plus anti-CD28, allogeneic immature or mature dendritic cells. This activity was inhibited by the addition of S1P. Enhanced T cell proliferation was observed when these cells were stimulated with the same stimuli, but were incubated in serum free media. Addition of S1P to serum free media reversed the stimulation of T cells induced by all stimuli, suggesting that S1P is an important inhibitory molecule present in the serum. T cell proliferation was also inhibited by the addition of dihydrosphingoisne 1-phosphate, sphingosine and ceramide, however, the latter two sphingolipids required higher concentrations than S1P. Pretreatment of T cells with pertussis toxin (PTX) blocked the inhibitory effect of S1P upon activation with PMA plus ionomycin, but not upon activation with anti-CD3 plus anti-CD28. This is corroborated with the down-regulation of S1P1 in T cells stimulated with anti-CD3 plus anti-CD28. Similarly, PTX did not affect the inhibitory effect of S1P on T cell proliferation when dendritic cells were used as stimuli. Further, S1P enhanced rather than decreased IL-2 and IFN- secretion by T cells stimulated with anti-CD3 plus anti-CD28. These results show differential effects of S1P on polyclonal T cell proliferation and cytokine secretion.
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