title: Intrahepatic activation of naive CD4+ T cells by liver-resident phagocytic cells.
abstract: Naive T cell activation is normally restricted to the lymphoid organs, in part because of their limited ability to migrate into the parenchyma of peripheral tissues. The liver vasculature is unique, however, and circulating leukocytes within the hepatic sinusoids have direct access to liver-resident cells, which include an abundant population of Kupffer cells. It is well accepted that recognition of cognate Ag within the liver leads to naive CD8(+) T cell activation in situ, but it is unclear whether the liver also supports naive CD4(+) T cell activation. In this study, we show that naive CD4(+) T cells can be activated to proliferate in the liver when cognate Ag expression is induced in hepatocytes by recombinant adeno-associated viral vectors. Ag-specific retention and activation of naive CD4(+) T cells within the liver are independent of lymphoid tissues but dependent on a clodronate liposome-sensitive population of liver-resident phagocytic cells. To our knowledge, this study provides the first unequivocal evidence that naive CD4(+) T cells can be activated in a nonlymphoid organ. It also gives critical insight into how CD4(+) T cells specific for Ag expressed in the liver are recruited to participate in protective or pathological responses during hepatotropic infections and autoimmune liver disease.
authors: Centenary Institute and University of Sydney, Newtown, New South Wales 2042, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital/University of Sydney, Camperdown, New South Wales 2050, Australia;
authors: Szun S
authors: SS
authors: Tay
authors: Centenary Institute and University of Sydney, Newtown, New South Wales 2042, Australia;
authors: Yik Chun
authors: YC
authors: Wong
authors: Centenary Institute and University of Sydney, Newtown, New South Wales 2042, Australia;
authors: Ben
authors: B
authors: Roediger
authors: Centenary Institute and University of Sydney, Newtown, New South Wales 2042, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital/University of Sydney, Camperdown, New South Wales 2050, Australia;
authors: Frederic
authors: F
authors: Sierro
authors: St. Vincent's Hospital, Fitzroy, Melbourne, Victoria 3065, Australia;
authors: Bo
authors: B
authors: Lu
authors: Centenary Institute and University of Sydney, Newtown, New South Wales 2042, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital/University of Sydney, Camperdown, New South Wales 2050, Australia;
authors: David M
authors: DM
authors: McDonald
authors: Centenary Institute and University of Sydney, Newtown, New South Wales 2042, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital/University of Sydney, Camperdown, New South Wales 2050, Australia;
authors: Claire M
authors: CM
authors: McGuffog
authors: Centenary Institute and University of Sydney, Newtown, New South Wales 2042, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital/University of Sydney, Camperdown, New South Wales 2050, Australia;
authors: Nicholas J
authors: NJ
authors: Meyer
authors: Gene Therapy Research Unit, Children's Medical Research Institute, The Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia;
authors: Ian E
authors: IE
authors: Alexander
authors: The John Curtin School of Medical Research, Canberra, Australian Capital Territory 0200, Australia;
authors: Ian A
authors: IA
authors: Parish
authors: Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia;
authors: William R
authors: WR
authors: Heath
authors: Centenary Institute and University of Sydney, Newtown, New South Wales 2042, Australia; Discipline of Dermatology, University of Sydney, Camperdown, New South Wales 2050, Australia; Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia; and.
authors: Wolfgang
authors: W
authors: Weninger
authors: Collaborative Transplantation Research Group, Bosch Institute, Royal Prince Alfred Hospital/University of Sydney, Camperdown, New South Wales 2006, Australia.
authors: G Alex
authors: GA
authors: Bishop
authors: Centenary Institute and University of Sydney, Newtown, New South Wales 2042, Australia;
authors: Jennifer R
authors: JR
authors: Gamble
authors: Centenary Institute and University of Sydney, Newtown, New South Wales 2042, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital/University of Sydney, Camperdown, New South Wales 2050, Australia;
authors: Geoffrey W
authors: GW
authors: McCaughan
authors: Centenary Institute and University of Sydney, Newtown, New South Wales 2042, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital/University of Sydney, Camperdown, New South Wales 2050, Australia; d.bowen@centenary.usyd.edu.au p.bertolino@centenary.org.au.
authors: Patrick
authors: P
authors: Bertolino
authors: Centenary Institute and University of Sydney, Newtown, New South Wales 2042, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital/University of Sydney, Camperdown, New South Wales 2050, Australia; Collaborative Transplantation Research Group, Bosch Institute, Royal Prince Alfred Hospital/University of Sydney, Camperdown, New South Wales 2006, Australia d.bowen@centenary.usyd.edu.au p.bertolino@centenary.org.au.
authors: David G
authors: DG
authors: Bowen
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D004002:Clodronic Acid / Q000494:pharmacology; D007728:Kupffer Cells / Q000276:immunology* / Q000473:pathology; D008081:Liposomes; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D050071:Bone Density Conservation Agents; D008081:Liposomes; D004002:Clodronic Acid