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Cutting Edge: Alternative Signaling of Th17 Cell Development by Sphingosine 1-Phosphate¹

Department of Medicine and Department of Microbiology-Immunology, University of California, San Francisco, CA 94143

Sphingosine 1-phosphate (S1P) in blood and lymph controls T cell traffic and proliferation through type 1 S1P receptor (S1P₁) signals, but suppression of IFN- generation has been the only consistently observed effect on T cell cytokines. The fact that S1P enhances the development of Th17 cells from Ag-challenged transgenic S1P₁-overexpressing CD4 T cells suggested that the S1P-S1P₁ axis may promote the expansion of Th17 cells in wild-type mice. In a model of Th17 cell development from CD4 T cells stimulated by anti-CD3 plus anti-CD28 Abs and a mixture of TGF-1, IL-1, and IL-6, S1P enhanced their number and IL-17-generating activity the same as IL-23. As for IL-23 enhancement of Th17 cell development, that by S1P was prevented by IL-4 plus IFN- and by IL-27. The prevention of S1P augmentation of Th17 cell development by the S1P receptor agonist and down-regulator FTY720 implies that FTY720 immunosuppression is attributable partially to inhibition of Th17-mediated inflammation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The research described was supported largely by National Institutes of Health Grant HL31809.

² Address correspondence and reprint requests to Dr. Edward J. Goetzl, Immunology-Allergy, Room UB8B, University of California Medical Center, 533 Parnassus at 4th Avenue, San Francisco, CA 94143-0711. E-mail address: edward.goetzl{at}ucsf.edu

³ Abbreviations used in this paper: S1P, sphingosine 1-phosphate; S1P₁, type 1 S1P G protein-coupled receptor; a-TCR, anti-TCR Ab; GPCR, G protein-coupled receptor; P-FTY720, phosphorylated FTY720.

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