title: Sema3e/Plexin D1 Modulates Immunological Synapse and Migration of Thymocytes by Rap1 Inhibition.
abstract: Regulation of thymocyte trafficking plays an important role during thymic selection, but our understanding of the molecular mechanisms underlying these processes is limited. In this study, we demonstrated that class III semaphorin E (sema3e), a guidance molecule during neural and vascular development, directly inhibited Rap1 activation and LFA-1-dependent adhesion through the GTPase-activating protein activity of plexin D1. Sema3e inhibited Rap1 activation of thymocytes in response to chemokines and TCR stimulation, LFA-mediated adhesion, and T cell-APC interactions. Immunological synapse (IS) formation in mature thymocytes on supported lipid bilayers was also attenuated by sema3e. Impaired IS formation was associated with reduced Rap1 activation on the contact surface and cell periphery. Moreover, a significant increase of CD4(+) thymocytes was detected in the medulla of mice with T cell lineage-specific deletion of plexin D1. Two-photon live imaging of thymic explants and slices revealed enhanced Rap1 activation and migration of CD69(+) double-positive and single-positive cells with plexin D1 deficiency. Our results demonstrate that sema3e/plexin D1 modulates IS formation and Ag-scanning activities of thymocytes within thymic tissues.
authors.affiliation: Department of Molecular Genetics, Kansai Medical University, Osaka 573-1010, Japan;
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Department of Molecular Genetics, Kansai Medical University, Osaka 573-1010, Japan;
authors.forename: Naoyuki
authors.identifier: http://orcid.org/0000-0002-6624-5989
authors.initials: N
authors.lastname: Kondo
authors.affiliation: Department of Molecular Genetics, Kansai Medical University, Osaka 573-1010, Japan;
authors.forename: Madoka
authors.initials: M
authors.lastname: Ozawa
authors.affiliation: Department of Urology and Andrology, Kansai Medical University, Osaka 573-1010, Japan; and.
authors.forename: Kaneki
authors.identifier: http://orcid.org/0000-0003-4942-5934
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Division of Gastroenterology and Hepatology, Third Department of Internal Medicine, Kansai Medical University, Osaka 573-1010, Japan.
authors.forename: Takashi
authors.identifier: http://orcid.org/0000-0002-4854-6649
authors.initials: T
authors.lastname: Tomiyama
authors.affiliation: Department of Molecular Genetics, Kansai Medical University, Osaka 573-1010, Japan; kinashi@hirakata.kmu.ac.jp.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kinashi
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D002450:Cell Communication; D002465:Cell Movement / Q000235:genetics; D018925:Chemokines / Q000378:metabolism; D003598:Cytoskeletal Proteins; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D054992:Immunological Synapses / Q000378:metabolism*; D056747:Immunomodulation; D047908:Intracellular Signaling Peptides and Proteins; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D039961:Semaphorins; D015398:Signal Transduction; D060168:Thymocytes / Q000276:immunology* / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000037:antagonists & inhibitors*
chemical_list: D018925:Chemokines; D003598:Cytoskeletal Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C473552:Plxnd1 protein, mouse; C111150:Sema3e protein, mouse; D039961:Semaphorins; D020744:rac GTP-Binding Proteins; D020827:rap1 GTP-Binding Proteins