Making and Breaking the Gradient

Science's STKE  13 Sep 2005:
Vol. 2005, Issue 301, pp. tw331
DOI: 10.1126/stke.3012005tw331

To combat infection, lymphocytes must first be "enticed" to leave their organ of residence and enter the circulation. The same is true for mature thymocytes that must exit the thymus to seed peripheral lymphoid organs. A dominant signal for lymphocyte egress comes from sphingosine 1-phosphate (S1P), although it remains to be established how this extracellular lipid mediator is itself regulated to control lymphocyte trafficking. Schwab et al. (see the Perspective by Hla) observe that a long-established inhibitor of thymocyte egress, the food colorant 2-acetyl-4-tetrahydroxybutylimidazole (THI), also inhibits lymphocyte migration and causes the accumulation of S1P in lymph nodes, which are otherwise low in S1P relative to the lymph and blood. This accumulation could be overcome with saturating levels of an essential cofactor for S1P lyase, an enzyme that degrades S1P, which suggests that THI works by preventing S1P breakdown. The maintenance of an S1P gradient between lymphoid tissues and the circulation by S1P lyase may provide a target for selective therapeutic immune suppression.

S. R. Schwab, J. P. Pereira, M. Matloubian, Y. Xu, Y. Huang, J. G. Cyster, Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 309, 1735-1739 (2005). [Abstract] [Full Text]

T. Hla, Dietary factors and immunological consequences. Science 309, 1682-1683 (2005). [Summary] [Full Text]