title: Invariant natural killer T cell deficiency leads to the development of spontaneous liver inflammation dependent on γδT cells in mice.
abstract: BACKGROUND
  Immune tolerance is maintained in the liver, and perturbation of tolerance can lead to immune-mediated liver diseases such as autoimmune hepatitis (AIH). Invariant natural killer T (iNKT) cells and γδT cells have been shown to maintain immune homeostasis as regulatory cells and to play pathogenic roles in immune-mediated diseases as effector cells. We hypothesized that iNKT cells and γδT cells are involved in the maintenance of hepatic immune tolerance and immune-mediated liver disease.
  
  
  METHODS
  We measured liver inflammation and the cytokine profiles of liver mononuclear cells in BALB/c wild-type (WT) mice and BALB/c Jα18-deficient (KO) mice lacking iNKT cells. We also examined the role of γδT cells in AIH using liver tissue from AIH patients and control subjects.
  
  
  RESULTS
  Spontaneous liver inflammation, hepatocyte damage, and anti-nuclear-antibody production occurred in Jα18 KO mice but not in WT mice. Furthermore, liver mononuclear cells from Jα18 KO mice, but not those from WT mice, produced interleukin-17 (IL-17). γδT cells were the primary producers of the cytokine, and they were more abundant in the livers of Jα18 KO mice than in those of WT mice. In Jα18 KO mice, the administration of anti-γδT-cell-receptor antibody abolished liver inflammation, hepatocyte damage, and IL-17 production. γδT cells accumulated in the livers of AIH patients but not in those of the control subjects.
  
  
  CONCLUSIONS
  Our results suggest a protective role for iNKT cells, a pathologic role for γδT cells, and an association between these cells in the pathogenesis of AIH.
authors: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors: Kumiko
authors: K
authors: Nishio
authors: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors: Takuya
authors: T
authors: Miyagi
authors: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors: Tomohide
authors: T
authors: Tatsumi
authors: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors: Kaori
authors: K
authors: Mukai
authors: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors: Yoshinobu
authors: Y
authors: Yokoyama
authors: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors: Teppei
authors: T
authors: Yoshioka
authors: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors: Ryotaro
authors: R
authors: Sakamori
authors: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors: Hayato
authors: H
authors: Hikita
authors: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors: Takahiro
authors: T
authors: Kodama
authors: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors: Satoshi
authors: S
authors: Shimizu
authors: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors: Minoru
authors: M
authors: Shigekawa
authors: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors: Takatoshi
authors: T
authors: Nawa
authors: Osaka Rosai Hospital, Osaka, Japan.
authors: Harumasa
authors: H
authors: Yoshihara
authors: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors: Naoki
authors: N
authors: Hiramatsu
authors: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors: Hiroyuki
authors: H
authors: Yamanaka
authors: Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors: Ken-Ichiro
authors: K
authors: Seino
authors: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan. takehara@gh.med.osaka-u.ac.jp.
authors: Tetsuo
authors: T
authors: Takehara
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006505:Hepatitis / Q000276:immunology*; D006520:Hepatitis, Animal / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis; D008099:Liver / Q000276:immunology; D008297:Male; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008875:Middle Aged; D055611:Natural Killer T-Cells / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D016692:Receptors, Antigen, T-Cell, gamma-delta
keywords: Autoimmune hepatitis; Interleukin-17; Invariant natural killer T cells; γδT cells