title: IL-17-Producing Vγ4+ γδ T Cells Require Sphingosine 1-Phosphate Receptor 1 for Their Egress from the Lymph Nodes under Homeostatic and Inflammatory Conditions.
abstract: Conventional αβ T cells require sphingosine 1-phosphate (S1P) receptor 1 (S1P1) for circulation through the lymph nodes (LN); however, it is unclear whether γδ 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 γδ T cells (Vγ4(+) and Vγ4(-) subsets) in the blood of mice. In contrast, IL-17(+)Vγ4(+), IL-17(+)Vγ4(-), and IL-17(-)Vγ4(-) subsets were significantly accumulated in the LN after 6 h of FTY720 treatment. By skin application of a synthetic TLR7/8 agonist, Vγ4(+) γδ 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 Vγ4(+) γδ T cells in the DLN and inhibited their infiltration into the inflamed skin. Similarly, FTY720 inhibited infiltration of Vγ4(+) γδ T cells into the CNS by their sequestration into the DLN in experimental autoimmune encephalomyelitis. Vγ4(+) γδ 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 Vγ4(+) γδ T cells. Our findings strongly suggest that IL-17-producing Vγ4(+) γδ 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 Vγ4(+) γδ T cells from the DLN may partly contribute the clinical therapeutic effects of FTY720 in relapsing multiple sclerosis.
authors.affiliation: Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, Kanagawa 227-0033, Japan; and.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, Kanagawa 227-0033, Japan; and.
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Seki
authors.affiliation: Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, Kanagawa 227-0033, Japan; and.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kataoka
authors.affiliation: Safety Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama 335-8505, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Takemoto
authors.affiliation: Safety Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama 335-8505, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Utsumi
authors.affiliation: Safety Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama 335-8505, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fukunari
authors.affiliation: Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, Kanagawa 227-0033, Japan; and.
authors.forename: Kunio
authors.initials: K
authors.lastname: Sugahara
authors.affiliation: Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, Kanagawa 227-0033, Japan; and Chiba.Kenji@mk.mt-pharma.co.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Chiba
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology; D003872:Dermatitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D006706:Homeostasis; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation; D020381:Interleukin-17 / Q000096:biosynthesis*; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D043484:Proprotein Convertases / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000819:agonists; D051200:Toll-Like Receptor 8 / Q000819:agonists
chemical_list: D007166:Immunosuppressive Agents; D020381:Interleukin-17; D016692:Receptors, Antigen, T-Cell, gamma-delta; D049349:Receptors, Lysosphingolipid; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1; D000068876:Fingolimod Hydrochloride