Medullary thymic epithelial cell depletion leads to autoimmune hepatitis

J Clin Invest. 2013 Aug;123(8):3510-24. doi: 10.1172/JCI65414. Epub 2013 Jul 15.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antibodies, Antinuclear / metabolism
  • Disease Models, Animal
  • Epithelial Cells / immunology
  • Epithelial Cells / pathology*
  • Hepatitis, Autoimmune / immunology
  • Hepatitis, Autoimmune / pathology*
  • Humans
  • Immune Tolerance
  • Liver / immunology
  • Liver / metabolism
  • Liver / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Plasma Cells / pathology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / transplantation
  • T-Lymphocytes, Regulatory / immunology
  • TNF Receptor-Associated Factor 6 / deficiency
  • TNF Receptor-Associated Factor 6 / genetics
  • Thymus Gland / immunology
  • Thymus Gland / pathology*

Substances

  • Antibodies, Antinuclear
  • TNF Receptor-Associated Factor 6