Medullary thymic epithelial cell depletion leads to autoimmune hepatitis
Anthony J. Bonito, Costica Aloman, M. Isabel Fiel, Nichole M. Danzl, Sungwon Cha, Erica G. Weinstein, Seihwan Jeong, Yongwon Choi, Matthew C. Walsh, Konstantina Alexandropoulos
Anthony J. Bonito, Costica Aloman, M. Isabel Fiel, Nichole M. Danzl, Sungwon Cha, Erica G. Weinstein, Seihwan Jeong, Yongwon Choi, Matthew C. Walsh, Konstantina Alexandropoulos
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Research Article Immunology

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

Anthony J. Bonito, Costica Aloman, M. Isabel Fiel, Nichole M. Danzl, Sungwon Cha, Erica G. Weinstein, Seihwan Jeong, Yongwon Choi, Matthew C. Walsh, Konstantina Alexandropoulos

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Figure 4

Traf6ΔTEC mice produce autoantibodies that bind to liver-specific proteins.

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Traf6ΔTEC mice produce autoantibodies that bind to liver-specific prote...
(A and B) Concentrations of different antibody isotypes (A) and total Ig (B) in the sera of 6- to 12-week-old WT and Traf6ΔTEC mice were determined by ELISA. n ≥ 8 per genotype. Data are pooled results from 3 independent experiments run in triplicates. Red bars represent mean. Bar graph represents mean + SEM. (C and D) Western blots of normal tissue lysates (100 μg) from Rag1–/– mice were incubated with sera (1:100) from WT and Traf6ΔTEC mice as shown, followed by horseradish peroxidase–conjugated anti–mouse IgG secondary antibody. Protein bands in C and D were visualized by chemiluminescence as described in Methods. Blots were stripped and reprobed with anti-Erk antibody (loading control). In C, blots were cut apart in order to be incubated with different sera, then reassembled (black lines). Arrows in D denote protein bands that are unique to the liver. Representative blots from 1 of at least 2 independent experiments are shown. Li, liver; Lu, lung; Sp, spleen; Ki, kidney. (E) Autoantibody concentrations in the sera of 6- to 12-week-old WT and Traf6ΔTEC mice, determined by ELISA. n ≥ 7 per genotype. Red bars represent mean. **P < 0.01; ***P < 0.001.