title: Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling.
abstract: OBJECTIVE
  Because of the lack of animal models developing spontaneous autoimmune hepatitis (AIH), the molecular mechanisms involved in the development of AIH are still unclear. This study aims to examine the regulatory roles of naturally arising CD4(+)CD25(+) regulatory T (Treg) cells and programmed cell death 1 (PD-1)-mediated signaling in the development of AIH.
  
  
  METHODS
  To induce a concurrent loss of Treg cells and PD-1-mediated signaling, neonatal thymectomy (NTx), which severely reduces the number of Treg cells, was performed on PD-1(-/-) mice. After the NTx, we performed histologic examination, assessed autoantibody production and infiltrating cells in the liver, and conducted adoptive transfer experiments.
  
  
  RESULTS
  In contrast to NTx mice and PD-1(-/-) mice, NTx-PD-1(-/-) mice produced antinuclear antibodies and developed fatal hepatitis characterized by a CD4(+) and CD8(+) T-cell infiltration invading the parenchyma with massive lobular necrosis. Induction of AIH in NTx-PD-1(-/-) mice was suppressed by transfer of Treg cells, even derived from PD-1(-/-) mice. Transfer of total but not CD4(+) T-cell-depleted splenocytes from NTx-PD-1(-/-) mice into RAG2(-/-) mice induced the development of severe hepatitis. In contrast, the transfer of CD8(+) T-cell-depleted splenocytes triggered only mononuclear infiltrates without massive necrosis of the parenchyma.
  
  
  CONCLUSIONS
  NTx-PD-1(-/-) mice are the first mouse model of spontaneous fatal AIH. The concurrent loss of Treg cells and PD-1-mediated signaling can induce the development of fatal AIH. Autoreactive CD4(+) T cells are essential for induction of AIH, whereas CD8(+) T cells play an important role in progression to fatal hepatic damage.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kido
authors.forename: Norihiko
authors.initials: N
authors.lastname: Watanabe
authors.forename: Taku
authors.initials: T
authors.lastname: Okazaki
authors.forename: Takuji
authors.initials: T
authors.lastname: Akamatsu
authors.forename: Junya
authors.initials: J
authors.lastname: Tanaka
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Saga
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nishio
authors.forename: Tasuku
authors.initials: T
authors.lastname: Honjo
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D034961:Antigens, Nuclear / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005756:Gastritis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D019693:Hepatitis, Autoimmune / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D061026:Programmed Cell Death 1 Receptor; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013934:Thymectomy
chemical_list: D000974:Antibodies, Antinuclear; D000943:Antigens, Differentiation; D034961:Antigens, Nuclear; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor