Immunology GPCR Versus Cytokine Receptor: Is One As Good As the Other?

John F. Foley

Science’s STKE, AAAS, Washington, DC 20005, USA

Th17 cells are a distinct lineage of CD4⁺ T helper (Th) cells that produce the cytokines IL-17 (interleukin-17) and IL-22 and are important in fighting infection but are also involved in mediating autoimmune disorders. The generation of Th17 cells is dependent on IL-6 and transforming growth factor- (TGF-), together with either IL-1 or tumor necrosis factor-. It is unclear whether IL-23 is necessary for Th17 cell development. Liao et al. examined the effect of sphingosine 1-phosphate (S1P) on the generation of Th17 cells. S1P, acting through its G protein-coupled receptor S1P₁, is known to affect the trafficking and proliferation of T cells. This group has previously shown that stimulation of transgenic CD4⁺ T cells expressing increased amounts of S1P₁ results in the production of more Th17 cells than does stimulation of control cells. In the current study, the authors demonstrated that the addition of S1P to cultures of mouse splenic CD4⁺ T cells (maintained in the absence of IL-23) that were activated by stimulation of the T cell antigen receptor in the presence of IL-6, IL-1, and TGF- resulted in the production of more IL-17 protein and a higher percentage of Th17 cells than in cultures that lacked S1P. A selective agonist of S1P₁, SEW2871, had the same effect. Separate activation cultures containing optimal concentrations of either S1P or IL-23 produced similar numbers of Th17 cells. S1P treatment suppressed the production of interferon- and IL-4, the signature cytokines of Th1 and Th2 cells, respectively. The effect of S1P on the generation of Th17 cells was blocked by inhibitors of phosphoinositide 3-kinase and nuclear factor B. Finally, the immunosuppressive agent FTY720, which can down-regulate S1P₁, inhibited S1P-mediated generation of Th17 cells. These results show that S1P can substitute for IL-23 in the development of Th17 cells and suggest that part of the immunosuppressive effect of FTY720 may be due to the inhibition of Th17 cell development.

J.-J. Liao, M.-C. Huang, E. J. Goetzl, Cutting edge: Alternative signaling of Th17 cell development by sphingosine 1-phosphate. J. Immunol. 178, 5425-5428 (2007). [PubMed]