Sphingosine 1-phosphate (S1P) is an extracellular signalling molecule that acts through S1P receptor 1 (S1P1)–S1P5 to promote the egress of lymphocytes from lymphoid organs into the blood and lymph. But whether S1P promotes egress directly is not known, and nor is the source of S1P. Now, Pappu and colleagues show that different sources supply S1P to the blood and lymph, and that S1P acts directly on lymphocytes to induce their egress.

In previous studies, contradictory results have been obtained using S1P1-deficient mice, S1P1 agonists and S1P1 antagonists. To address these issues, Pappu and colleagues used a conditional-gene-deletion strategy to generate mice lacking both sphingosine kinase 1 (SPHK1) and SPHK2, the two enzymes that control S1P production. S1P was not detected in the plasma nor in the lymph of mice deficient in both SPHK1 and SPHK2. Furthermore, high levels of S1P1 were detected on lymphocytes in the blood and lymph compared with control mice, which, as ligand engagement leads to receptor downregulation, is consistent with the lack of S1P in these mice. T-cell numbers in the thymus were higher than in control mice, consistent with a role for S1P in controlling the exit of T cells from the thymus.

The authors next examined the source of extracellular S1P and found that plasma S1P is generated by haematopoietic cells, whereas lymph S1P is supplied by radiation-resistant cells at the site of egress. Previous studies had pointed to platelets as a possible source of plasma S1P, but mice that lack platelets have normal levels of plasma S1P. The authors found instead that red blood cells are a source of plasma S1P — transfer of wild-type red blood cells into mice that were deficient in both kinases restored plasma S1P levels within 36 hours. Further experiments showed that plasma S1P promotes lymphocyte egress from the spleen and thymus in a direct manner and is dependent on expression of S1P1 by lymphocytes.

These results shed further light on the ways in which S1P signalling controls the exit of lymphocytes from lymphoid organs and might help improve our understanding of the immunosuppressive action of molecules that target this system in clinical settings.

Author: Elaine Bell - Copyright © 2007 Nature Publishing Group, a division of MacMillan Publishers Limited; used with permission