title: Dual functions of Rap1 are crucial for T-cell homeostasis and prevention of spontaneous colitis.
abstract: Rap1-GTP activates leukocyte function-associated antigen-1 (LFA-1) to induce arrest on the high endothelial venule (HEV). Here we show that Rap1-GDP restrains rolling behaviours of T cells on the peripheral lymph node addressin (PNAd), P-selectin and mucosal addressin cell adhesion molecule-1 (MadCAM-1) by inhibiting tether formation. Consequently, Rap1 deficiency impairs homing of naive T cells to peripheral lymph nodes, but accelerates homing of TH17 and TH1 cells to the colon, resulting in spontaneous colitis with tumours. Rap1-GDP associates with and activates lymphocyte-oriented kinase, which phosphorylates ERM (ezrin, radixin and moesin) in resting T cells. Phosphomimetic ezrin reduces the rolling of Rap1-deficient cells, and thereby decreases their homing into the colon. On the other hand, chemokines activate Rap1 at the plasma membrane within seconds, and Rap1-GTP binds to filamins, which diminishes its association with the β2 chain of LFA-1 and results in LFA-1 activation. This Rap1-dependent regulation of T-cell circulation prevents the onset of colitis.
authors.affiliation: Department of Biosciences, School of Science, Kitasato University, 1-15-1 Kitasato, Minamiku, Sagamihara, Kanagawa 252-0373, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Ishihara
authors.affiliation: Department of Biosciences, School of Science, Kitasato University, 1-15-1 Kitasato, Minamiku, Sagamihara, Kanagawa 252-0373, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nishikimi
authors.affiliation: Department of Microbiology and Immunology, Laboratory of Immune Regulation, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Umemoto
authors.affiliation: Interdisciplinary Program for Biomedical Sciences, Institute for Academic Initiatives, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Masayuki
authors.identifier: http://orcid.org/0000-0001-6122-5201
authors.initials: M
authors.lastname: Miyasaka
authors.affiliation: Department of Pathology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Minamiku, Sagamihara, Kanagawa 252-0373, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Saegusa
authors.affiliation: Department of Biosciences, School of Science, Kitasato University, 1-15-1 Kitasato, Minamiku, Sagamihara, Kanagawa 252-0373, Japan.
authors.forename: Koko
authors.initials: K
authors.lastname: Katagiri
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology; D002465:Cell Movement; D003092:Colitis / Q000235:genetics / Q000276:immunology*; D005260:Female; D006706:Homeostasis; D006801:Humans; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D020668:rap GTP-Binding Proteins / Q000235:genetics / Q000276:immunology*; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000954:Antigens, Surface; C069886:L-selectin counter-receptors; D008565:Membrane Proteins; C492136:Rap1b protein, mouse; D020668:rap GTP-Binding Proteins; D020827:rap1 GTP-Binding Proteins