Medullary thymic epithelial cell depletion leads to autoimmune hepatitis

被引:65
作者
Bonito, Anthony J. [1 ]
Aloman, Costica [2 ]
Fiel, M. Isabel [3 ]
Danzl, Nichole M. [4 ]
Cha, Sungwon [1 ]
Weinstein, Erica G. [1 ]
Jeong, Seihwan [1 ]
Choi, Yongwon [5 ]
Walsh, Matthew C. [5 ]
Alexandropoulos, Konstantina [1 ]
机构
[1] Mt Sinai, Icahn Sch Med, Dept Med Clin Immunol, New York, NY 10029 USA
[2] Mt Sinai, Icahn Sch Med, Dept Med Liver Dis, New York, NY 10029 USA
[3] Mt Sinai, Icahn Sch Med, Dept Pathol, New York, NY 10029 USA
[4] Columbia Univ, Med Ctr, Ctr Translat Immunol, New York, NY USA
[5] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA
关键词
REGULATORY T-CELLS; SOLUBLE LIVER ANTIGEN; PROMISCUOUS GENE-EXPRESSION; SELF-TOLERANCE; ANIMAL-MODELS; AIRE; DISEASE; ANTIBODIES; TYPE-1; TRANSPLANTATION;
D O I
10.1172/JCI65414
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
100103 [病原生物学]; 100218 [急诊医学];
摘要
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 (Traf6 Delta TEC mice) showed a surprisingly narrow spectrum of autoimmunity affecting the liver. The liver inflammation in Traf6 Delta TEC 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 Traf6 Delta TEC 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 Traf6 Delta TEC 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.
引用
收藏
页码:3510 / 3524
页数:15
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