IL-17-Producing V gamma 4+ gamma delta T Cells Require Sphingosine 1-Phosphate Receptor 1 for Their Egress from the Lymph Nodes under Homeostatic and Inflammatory Conditions

Conventional alpha beta T cells require sphingosine 1-phosphate (S1P) receptor 1 (S1P1) for circulation through the lymph nodes (LN); however, it is unclear whether gamma delta 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 gamma delta T cells (V gamma 4+ and V gamma 4- subsets) in the blood of mice. In contrast, IL-17+V gamma 4+, IL-17+V gamma 4-, and IL-17-V gamma 4- subsets were significantly accumulated in the LN after 6 h of FTY720 treatment. By skin application of a synthetic TLR7/8 agonist, V gamma 4+ gamma delta 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 V gamma 4+ gamma delta T cells in the DLN and inhibited their infiltration into the inflamed skin. Similarly, FTY720 inhibited infiltration of V gamma 4+ gamma delta T cells into the CNS by their sequestration into the DLN in experimental autoimmune encephalomyelitis. V gamma 4+ gamma delta 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 V gamma 4+ gamma delta T cells. Our findings strongly suggest that IL-17-producing V gamma 4+ gamma delta 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 V gamma 4+ gamma delta T cells from the DLN may partly contribute the clinical therapeutic effects of FTY720 in relapsing multiple sclerosis.