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IL-17-Producing V4+ T Cells Require Sphingosine 1-Phosphate Receptor 1 for Their Egress from the Lymph Nodes under Homeostatic and Inflammatory Conditions

Maeda, Y;Seki, N;Kataoka, H;Takemoto, K;Utsumi, H;Fukunari, A;Sugahara, K;Chiba, K;

Conventional T cells require sphingosine 1-phosphate (S1P) receptor 1 (S1P1) for circulation through the lymph nodes (LN); however, it is unclear whether T cells use similar mechanisms. In this study, we found that treatment with fingolimod (FTY720, 1 mg/kg, orally) markedly reduced not only conventional CD4 T cells but also circulating T cells (V4(+) and V4(-) subsets) in the blood of mice. In contrast, IL-17(+)V4(+), IL-17(+)V4(-), and IL-17(-)V4(-) subsets were significantly accumulated in the LN after 6 h of FTY720 treatment. By skin application of a synthetic TLR7/8 agonist, V4(+) T cells (IL-17(+) and IL-17(-) subsets) were accumulated and expanded in the draining LN (DLN), whereas the IL-17(+) subset predominantly migrated to the inflamed skin. FTY720 induced a marked sequestration of IL-17-producing V4(+) T cells in the DLN and inhibited their infiltration into the inflamed skin. Similarly, FTY720 inhibited infiltration of V4(+) T cells into the CNS by their sequestration into the DLN in experimental autoimmune encephalomyelitis. V4(+) T cells expressed a significant level of S1P1 and showed a migratory response toward S1P. FTY720 treatment induced almost complete downregulation of S1P1 expression and S1P responsiveness in V4(+) T cells. Our findings strongly suggest that IL-17-producing V4(+) T cells require S1P1 for their egress from the LN under homeostatic and inflammatory conditions. Consequently, inhibition of S1P1-dependent egress of pathogenic IL-17-producing V4(+) T cells from the DLN may partly contribute the clinical therapeutic effects of FTY720 in relapsing multiple sclerosis.