FTY720, a sphingosine 1-phosphate receptor modulator, inhibits CD1d-restricted NKT cells by suppressing cytokine production but not migration

FTY720, a sphingosine 1-phosphate (S1P) receptor modulator, suppresses immune responses by inhibiting T-cell migration into target tissues; however, it does not alter T-cell functions. In this study, we investigated the biological effects of FTY720 on NKT cells. Unlike T cells, FTY720 suppressed the production of IL-4, IFN-gamma, IL-10, and IL-13 by NKT cells through the S1P1 receptor (S1P1). Moreover, FTY720 also inhibited the expression of T-bet and GATA-3 of NKT cells in the presence of TCR engagement. However, it did not inhibit NKT cell migration in vitro or in vivo. In a K/BxN serum transfer arthritis model, FTY720 suppressed arthritis in B6, but not in CD1d(-/-) mice. Moreover, the adoptive transfer of control NKT cells restored arthritis in CD1d(-/-) mice, whereas FTY720-pretreated NKT cells did not. The number of NKT cells in the joints of B6 mice given FTY720 was similar to that in the joints of untreated B6 mice, whereas the production of IL-4 and IFN-g was reduced in the FTY720-treated B6 mice. Taken together, these data show that FTY720 suppresses cytokine production in NKT cells through S1P1, but not NKT cell migration. Thus, FTY720 may be useful in the treatment of NKT cell-promoted immune diseases. Laboratory Investigation (2010) 90, 9-19; doi:10.1038/labinvest.2009.109; published online 12 October 2009