title: Autotaxin produced by stromal cells promotes LFA-1-independent and Rho-dependent interstitial T cell motility in the lymph node paracortex.
abstract: T cells exhibit high-speed migration within the paracortical T zone of lymph nodes (LNs) as they scan cognate Ags displayed by dendritic cells in the tissue microenvironment supported by the network of stromal cells. Although intranodal T cell migration is controlled in part by chemokines and LFA-1/ICAM-1, the mechanisms underlying their migratory activity independent of these factors remain to be elucidated. In this study, we show that LN stromal cells constitutively express autotaxin (ATX), an ectoenzyme that is important for the generation of lysophosphatidic acid (LPA). Importantly, CCL21(+) stromal cells in the T zone produced and immobilized ATX on their cell surface. Two-photon imaging using LN tissue slices revealed that pharmacological inhibition of ATX or LPA receptors significantly reduced T cell migration, and this was further exacerbated by blockage of Gαi signaling or LFA-1. Therefore, T cell motility mediated by the ATX-LPA axis was independent of Gαi and LFA-1. LPA induced slow intermittent movement of T cells in vitro in a LFA-1-independent manner and enhanced CCL21-induced migration. Moreover, LPA and CCL21 cooperatively augmented RhoA activity in T cells, which was necessary for efficient intranodal T cell migration via the downstream ROCK-myosin II pathway. Taken together, T zone stromal cells control optimal migratory behavior of T cells via multiple signaling cues mediated by chemokines and ATX/LPA.
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka 573-1010, Japan katakait@hirakata.kmu.ac.jp.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Katakai
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka 573-1010, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kondo
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka 573-1010, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka 573-1010, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kinashi
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D054421:Chemokine CCL21 / Q000494:pharmacology; D005260:Female; D007555:Isoxazoles / Q000494:pharmacology; D008198:Lymph Nodes / Q000276:immunology* / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D036641:Microscopy, Fluorescence, Multiphoton; D024462:Myosin Type II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D063065:Organophosphonates / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D017154:Stromal Cells / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D059467:Transcriptome / Q000235:genetics / Q000276:immunology; D054460:rho-Associated Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000099189:Lysophospholipase D
chemical_list: D000813:Anilides; D054421:Chemokine CCL21; D007555:Isoxazoles; D016169:Lymphocyte Function-Associated Antigen-1; D008246:Lysophospholipids; D024462:Myosin Type II; D063065:Organophosphonates; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D000099189:Lysophospholipase D; C533861:(4-(tetradecanoylamino)benzyl)phosphonic acid; C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; C032881:lysophosphatidic acid