title: Dysregulated generation of follicular helper T cells in the spleen triggers fatal autoimmune hepatitis in mice.
abstract: OBJECTIVE
  To clarify mechanisms involved in the development of autoimmune hepatitis (AIH), we recently developed a mouse model of spontaneous AIH by inducing a concurrent loss of Foxp3(+) regulatory T cells and programmed cell death 1 (PD-1)-mediated signaling. Fatal AIH in these mice was characterized by severe T-cell infiltration and huge production of antinuclear antibodies (Abs). This study aims to identify induction sites, responsible T-cell subsets, and key molecules for induction of AIH.
  
  
  METHODS
  To develop the mouse model of AIH, neonatal thymectomy (NTx) was performed on PD-1-deficient (PD-1(-/-)) mice. We then conducted neonatal splenectomy or in vivo administration of Abs to cytokines, chemokines, or cell-surface molecules.
  
  
  RESULTS
  In NTx-PD-1(-/-) mice, either neonatal splenectomy or in vivo CD4(+) T-cell depletion suppressed CD4(+) and CD8(+) T-cell infiltration in the liver. In the induction phase of AIH, splenic CD4(+) T cells were localized in B-cell follicles with huge germinal centers and showed the Bcl6(+) inducible costimulator (ICOS)(+) interleukin (IL)-21(+) IL-21 receptor (IL-21R)(+) follicular helper T (T(FH)) cell phenotype. Blocking Abs to ICOS or IL-21 suppressed T(FH)-cell generation and induction of AIH. In addition, IL-21 produced by T(FH) cells drove CD8(+) T-cell activation. Splenic T(FH) cells and CD8(+) T cells expressed CCR6, and CCL20 expression was elevated in the liver. Administration of anti-CCL20 suppressed migration of these T cells to the liver and induction of AIH.
  
  
  CONCLUSIONS
  Dysregulated T(FH) cells in the spleen are responsible for the induction of fatal AIH, and CCR6-CCL20 axis-dependent migration of splenic T cells is crucial to induce AIH in NTx-PD-1(-/-) mice.
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan. norihiko@kuhp.kyoto-u.ac.jp
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Aoki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kido
authors.forename: Satoru
authors.initials: S
authors.lastname: Iwamoto
authors.forename: Hisayo
authors.initials: H
authors.lastname: Nishiura
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Maruoka
authors.forename: Junya
authors.initials: J
authors.lastname: Tanaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Taku
authors.initials: T
authors.lastname: Okazaki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
authors.forename: Norihiko
authors.initials: N
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000276:immunology; D054418:Chemokine CCL20 / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D019693:Hepatitis, Autoimmune / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D061026:Programmed Cell Death 1 Receptor; D054399:Receptors, CCR6 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology* / Q000601:surgery; D013156:Splenectomy; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology*; D013934:Thymectomy; D000098546:Interleukin-21
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; C493447:CCL20 protein, mouse; C498126:CCR6 protein, mouse; D054418:Chemokine CCL20; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D054399:Receptors, CCR6; D000098546:Interleukin-21