title: Core Fucosylation on T Cells, Required for Activation of T-Cell Receptor Signaling and Induction of Colitis in Mice, Is Increased in Patients With Inflammatory Bowel Disease.
abstract: Attachment of a fucose molecule to the innermost N-glycan in a glycoprotein (core fucosylation) regulates the activity of many growth factor receptors and adhesion molecules. The process is catalyzed by α1-6 fucosyltransferase (FUT8) and required for immune regulation, but it is not clear whether this process is dysregulated during disease pathogenesis. We investigated whether core fucosylation regulates T-cell activation and induction of colitis in mice, and is altered in patients with inflammatory bowel disease (IBD).
  
  
  
  Biopsy samples were collected from inflamed and noninflamed regions of intestine from patients (8 with Crohn's disease, 4 with ulcerative colitis, and 4 without IBD [controls]) at Osaka University Hospital. Colitis was induced in FUT8-deficient (Fut8(-/-)) mice and Fut8(+/+) littermates by administration of trinitrobenzene sulfonic acid. Intestinal tissues were collected and analyzed histologically. Immune cells were collected and analyzed by lectin flow cytometry, immunofluorescence, and reverse-transcription polymerase chain reaction, as well as for production of cytokines and levels of T-cell receptor (TCR) in lipid raft fractions. T-cell function was analyzed by intraperitoneal injection of CD4(+)CD62L(+) naïve T cells into RAG2-deficient mice.
  
  
  
  Levels of core fucosylation were increased on T cells from mice with colitis, compared with mice without colitis, as well as on inflamed mucosa from patients with IBD, compared with their noninflamed tissues or tissues from control patients. Fut8(-/-) mice developed less-severe colitis than Fut8(+/+) mice, and T cells from Fut8(-/-) mice produced lower levels of T-helper 1 and 2 cytokines. Adoptive transfer of Fut8(-/-) T cells to RAG2-deficient mice reduced the severity of colitis. Compared with CD4(+) T cells from Fut8(+/+) mice, those from Fut8(-/-) mice expressed similar levels of TCR and CD28, but these proteins did not contain core fucosylation. TCR complexes formed on CD4(+) T cells from Fut8(-/-) mice did not signal properly after activation and were not transported to lipid rafts.
  
  
  
  Core fucosylation of the TCR is required for T-cell signaling and production of inflammatory cytokines and induction of colitis in mice. Levels of TCR core fucosylation are increased on T cells from intestinal tissues of patients with IBD; this process might be blocked as a therapeutic strategy.
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Fujii
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Shinzaki
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Iijima
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Wakamatsu
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Chizuru
authors.initials: C
authors.lastname: Iwamoto
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Sobajima
authors.affiliation: Research Center for Ultra-High Voltage Electron Microscopy, Osaka University, Osaka, Japan.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Kuwahara
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hiyama
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takamatsu
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Uozumi
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan; Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kamada
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tsujii
authors.affiliation: Disease Glycomics Team, RIKEN, Saitama, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taniguchi
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan. Electronic address: emiyoshi@sahs.med.osaka-u.ac.jp.
authors.forename: Eiji
authors.initials: E
authors.lastname: Miyoshi
mesh_terms: D019264:Adoptive Transfer; D000328:Adult; D000818:Animals; D001706:Biopsy; D016022:Case-Control Studies; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005643:Fucose / Q000378:metabolism; D005647:Fucosyltransferases / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D005643:Fucose; D005647:Fucosyltransferases; C020559:Glycoprotein 6-alpha-L-fucosyltransferase
keywords: Activation; Glycosylation; Oligosaccharide; T-Cell Signaling