title: Hepatocyte entry leads to degradation of autoreactive CD8 T cells.
abstract: Although most self-reactive T cells are eliminated in the thymus, mechanisms to inactivate or control T cells specific for extrathymic antigens are required and exist in the periphery. By investigating the site in which autoreactive T cells are tolerized, we identify a unique mechanism of peripheral deletion in which naïve autoreactive CD8 T cells are rapidly eliminated in the liver after intrahepatic activation. T cells actively invade hepatocytes, enter endosomal/lysosomal compartments, and are degraded. Blockade of this process leads to accumulation of autoreactive CD8 T cells in the liver and breach of tolerance, with the development of autoimmune hepatitis. Cell into cell invasion, or emperipolesis, is a long-observed phenomenon for which a physiological role has not been previously demonstrated. We propose that this "suicidal emperipolesis" is a unique mechanism of autoreactive T-cell deletion, a process critical for the maintenance of tolerance.
authors.affiliation: Centenary Institute and AW Morrow Gastroenterology and Liver Centre, Royal Price Alfred Hospital, University of Sydney, Newtown, NSW 2042, Australia.
authors.forename: Volker
authors.initials: V
authors.lastname: Benseler
authors.forename: Alessandra
authors.initials: A
authors.lastname: Warren
authors.forename: Michelle
authors.initials: M
authors.lastname: Vo
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Holz
authors.forename: Szun S
authors.initials: SS
authors.lastname: Tay
authors.forename: David G
authors.initials: DG
authors.lastname: Le Couteur
authors.forename: Eamon
authors.initials: E
authors.lastname: Breen
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Allison
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Claire
authors.initials: C
authors.lastname: McGuffog
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Schlitt
authors.forename: David G
authors.initials: DG
authors.lastname: Bowen
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: McCaughan
authors.forename: Patrick
authors.initials: P
authors.lastname: Bertolino
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016923:Cell Death / Q000276:immunology*; D057687:Emperipolesis / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D061166:Peripheral Tolerance / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C064658:RAG-1 protein