title: Medullary thymic epithelial cell depletion leads to autoimmune hepatitis.
abstract: TRAF6, an E3 ubiquitin protein ligase, plays a critical role in T cell tolerance by regulating medullary thymic epithelial cell (mTEC) development. mTECs regulate T cell tolerance by ectopically expressing self-antigens and eliminating autoreactive T cells in the thymus. Here we show that mice with mTEC depletion due to conditional deletion of Traf6 expression in murine thymic epithelial cells (Traf6ΔTEC mice) showed a surprisingly narrow spectrum of autoimmunity affecting the liver. The liver inflammation in Traf6ΔTEC mice exhibited all the histological and immunological characteristics of human autoimmune hepatitis (AIH). The role of T cells in AIH establishment was supported by intrahepatic T cell population changes and AIH development after transfer of liver T cells into immunodeficient mice. Despite a 50% reduction in natural Treg thymic output, peripheral tolerance in Traf6ΔTEC mice was normal, whereas compensatory T regulatory mechanisms were evident in the liver of these animals. These data indicate that mTECs exert a cell-autonomous role in central T cell tolerance and organ-specific autoimmunity, but play a redundant role in peripheral tolerance. These findings also demonstrate that Traf6ΔTEC mice are a relevant model with which to study the pathophysiology of AIH, as well as autoantigen-specific T cell responses and regulatory mechanisms underlying this disease.
authors.affiliation: Department of Medicine/Clinical Immunology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Bonito
authors.forename: Costica
authors.initials: C
authors.lastname: Aloman
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Fiel
authors.forename: Nichole M
authors.initials: NM
authors.lastname: Danzl
authors.forename: Sungwon
authors.initials: S
authors.lastname: Cha
authors.forename: Erica G
authors.initials: EG
authors.lastname: Weinstein
authors.forename: Seihwan
authors.initials: S
authors.lastname: Jeong
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Walsh
authors.forename: Konstantina
authors.initials: K
authors.lastname: Alexandropoulos
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000974:Antibodies, Antinuclear / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology*; D019693:Hepatitis, Autoimmune / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007108:Immune Tolerance; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010950:Plasma Cells / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D048029:TNF Receptor-Associated Factor 6 / Q000172:deficiency / Q000235:genetics; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology*
chemical_list: D000974:Antibodies, Antinuclear; D048029:TNF Receptor-Associated Factor 6