title: Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses.
abstract: CD8 T-cell responses to liver-expressed antigens range from deletional tolerance to full effector differentiation resulting in overt hepatotoxicity. The reasons for these heterogeneous outcomes are not well understood. To identify factors that govern the fate of CD8 T cells activated by hepatocyte-expressed antigen, we exploited recombinant adenoassociated viral vectors that enabled us to vary potential parameters determining these outcomes in vivo. Our findings reveal a threshold of antigen expression within the liver as the dominant factor determining T-cell fate, irrespective of T-cell receptor affinity or antigen cross-presentation. Thus, when a low percentage of hepatocytes expressed cognate antigen, high-affinity T cells developed and maintained effector function, whereas, at a high percentage, they became functionally exhausted and silenced. Exhaustion was not irreversibly determined by initial activation, but was maintained by high intrahepatic antigen load during the early phase of the response; cytolytic function was restored when T cells primed under high antigen load conditions were transferred into an environment of low-level antigen expression. Our study reveals a hierarchy of factors dictating the fate of CD8 T cells during hepatic immune responses, and provides an explanation for the different immune outcomes observed in a variety of immune-mediated liver pathologic conditions.
authors.affiliation: Liver Immunology Group and AW Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, Newtown, NSW 2042, Australia;Immune Imaging Group, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, Newtown, NSW 2042 Australia;
authors.forename: Szun Szun
authors.initials: SS
authors.lastname: Tay
authors.affiliation: Liver Immunology Group and AW Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, Newtown, NSW 2042, Australia;
authors.forename: Yik Chun
authors.initials: YC
authors.lastname: Wong
authors.affiliation: Liver Immunology Group and AW Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, Newtown, NSW 2042, Australia;
authors.forename: David M
authors.initials: DM
authors.lastname: McDonald
authors.affiliation: Liver Immunology Group and AW Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, Newtown, NSW 2042, Australia;
authors.forename: Nicole A W
authors.initials: NA
authors.lastname: Wood
authors.affiliation: Immune Imaging Group, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, Newtown, NSW 2042 Australia;
authors.forename: Ben
authors.initials: B
authors.lastname: Roediger
authors.affiliation: Liver Immunology Group and AW Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, Newtown, NSW 2042, Australia;
authors.forename: Frederic
authors.initials: F
authors.lastname: Sierro
authors.affiliation: Liver Immunology Group and AW Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, Newtown, NSW 2042, Australia;
authors.forename: Claire
authors.initials: C
authors.lastname: Mcguffog
authors.affiliation: Gene Therapy Research Unit, Children's Medical Research Institute and Children's Hospital at Westmead, Westmead, NSW 2145, Australia;
authors.forename: Ian E
authors.initials: IE
authors.lastname: Alexander
authors.affiliation: Collaborative Transplantation Research Group, Bosch Institute, Royal Prince Alfred Hospital and University of Sydney, Newtown, NSW 2042, Australia;
authors.forename: G Alex
authors.initials: GA
authors.lastname: Bishop
authors.affiliation: Vascular Biology Group, Centenary Institute and University of Sydney, Newtown, NSW 2042, Australia; and.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Gamble
authors.affiliation: Immune Imaging Group, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, Newtown, NSW 2042 Australia;Discipline of Dermatology, University of Sydney, Camperdown, NSW 2006, Australia.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weninger
authors.affiliation: Liver Immunology Group and AW Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, Newtown, NSW 2042, Australia;
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: McCaughan
authors.affiliation: Liver Immunology Group and AW Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, Newtown, NSW 2042, Australia; p.bertolino@centenary.org.au d.bowen@centenary.usyd.edu.au.
authors.forename: Patrick
authors.initials: P
authors.lastname: Bertolino
authors.affiliation: Liver Immunology Group and AW Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, Newtown, NSW 2042, Australia;Collaborative Transplantation Research Group, Bosch Institute, Royal Prince Alfred Hospital and University of Sydney, Newtown, NSW 2042, Australia; p.bertolino@centenary.org.au d.bowen@centenary.usyd.edu.au.
authors.forename: David G
authors.initials: DG
authors.lastname: Bowen
mesh_terms: D000818:Animals; D000941:Antigens / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D022781:Hepatocytes / Q000166:cytology / Q000276:immunology*; D008099:Liver / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D000941:Antigens
keywords: CTL; TCR; cytotoxicity; rAAV