| First Author | Bonito AJ | Year | 2013 |
| Journal | J Clin Invest | Volume | 123 |
| Issue | 8 | Pages | 3510-24 |
| PubMed ID | 23867620 | Mgi Jnum | J:201400 |
| Mgi Id | MGI:5514068 | Doi | 10.1172/JCI65414 |
| Citation | Bonito AJ, et al. (2013) Medullary thymic epithelial cell depletion leads to autoimmune hepatitis. J Clin Invest 123(8):3510-24 |
| abstractText | 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 (Traf6DeltaTEC mice) showed a surprisingly narrow spectrum of autoimmunity affecting the liver. The liver inflammation in Traf6DeltaTEC 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 Traf6DeltaTEC 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 Traf6DeltaTEC 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. |
