title: Effector T cell function rather than survival determines extent and duration of hepatitis in mice.
abstract: Acute hepatitis is often mediated by cytotoxic T lymphocytes (CTLs); however, the intrinsic parameters that limit CTL-mediated liver injury are not well understood.
  
  
  
  To investigate whether acute liver damage is limited by molecules that decrease the lifespan or effector function of CTLs, we used a well-characterized transgenic (Tg) mouse model in which acute liver damage develops upon transfer of T cell receptor (TCR) Tg CD8 T cells. Recipient Tg mice received donor TCR Tg T cells deficient for either the pro-apoptotic molecule Bim, which regulates CTL survival, or suppressor of cytokine signaling-1 (SOCS-1), which controls expression of common gamma chain cytokines; the effects of anti-PD-L1 neutralizing antibodies were also assessed.
  
  
  
  Use of Bim-deficient donor T cells and/or PD-L1 blockade increased the number of intrahepatic T cells without affecting the degree and kinetic of acute hepatitis. In contrast, SOCS-1-deficient T cells induced a heightened, prolonged acute hepatitis caused by their enhanced cytotoxic function and increased expansion. Although they inflicted more severe acute liver damage, SOCS-1-deficient T cells never precipitated chronic hepatitis and became exhausted.
  
  
  
  The degree of acute hepatitis is regulated by the function of CD8 T cells, but is not affected by changes in CTL lifespan. Although manipulation of the examined parameters affected acute hepatitis, persistent hepatitis did not ensue, indicating that, in the presence of high intrahepatic antigen load, changes in these factors in isolation were not sufficient to prevent T cell exhaustion and mediate progression to chronic hepatitis.
authors.affiliation: Liver Immunology Program, Centenary Institute, Newtown, NSW, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital Newtown, NSW, and Faculty of Medicine, University of Sydney, NSW, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Vo
authors.affiliation: Liver Immunology Program, Centenary Institute, Newtown, NSW, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital Newtown, NSW, and Faculty of Medicine, University of Sydney, NSW, Australia; Current address: Department of Microbiology and Immunology, The Peter Doherty Institute, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Holz
authors.affiliation: Liver Immunology Program, Centenary Institute, Newtown, NSW, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital Newtown, NSW, and Faculty of Medicine, University of Sydney, NSW, Australia.
authors.forename: Yik Chun
authors.initials: YC
authors.lastname: Wong
authors.affiliation: Liver Immunology Program, Centenary Institute, Newtown, NSW, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital Newtown, NSW, and Faculty of Medicine, University of Sydney, NSW, Australia.
authors.forename: Kieran
authors.initials: K
authors.lastname: English
authors.affiliation: Liver Immunology Program, Centenary Institute, Newtown, NSW, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital Newtown, NSW, and Faculty of Medicine, University of Sydney, NSW, Australia; Current address: Department of Surgery, University of Regensburg, Bavaria, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Benseler
authors.affiliation: Liver Immunology Program, Centenary Institute, Newtown, NSW, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital Newtown, NSW, and Faculty of Medicine, University of Sydney, NSW, Australia.
authors.forename: Claire
authors.initials: C
authors.lastname: McGuffog
authors.affiliation: Department of Molecular Immunology Graduate School, Tokyo Medical and Dental University, Yushima, Tokyo, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.affiliation: AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital Newtown, NSW, and Faculty of Medicine, University of Sydney, NSW, Australia; Liver Injury and Cancer Program, Centenary Institute, Newtown, NSW, Australia.
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: McCaughan
authors.affiliation: Liver Immunology Program, Centenary Institute, Newtown, NSW, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital Newtown, NSW, and Faculty of Medicine, University of Sydney, NSW, Australia. Electronic address: d.bowen@centenary.org.au.
authors.forename: David G
authors.initials: DG
authors.lastname: Bowen
authors.affiliation: Liver Immunology Program, Centenary Institute, Newtown, NSW, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital Newtown, NSW, and Faculty of Medicine, University of Sydney, NSW, Australia. Electronic address: p.bertolino@centenary.org.au.
authors.forename: Patrick
authors.initials: P
authors.lastname: Bertolino
mesh_terms: D000208:Acute Disease; D000818:Animals; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000502:physiology; D000072224:Bcl-2-Like Protein 11 / Q000502:physiology; D002470:Cell Survival; D006505:Hepatitis / Q000209:etiology* / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000502:physiology
chemical_list: D060890:B7-H1 Antigen; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C498919:Cd274 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein
keywords: Autoimmunity; Liver; Tolerance; Transgenic