Regulation of medullary thymic epithelial cell differentiation and function by the signaling protein Sin

Danzl, Nichole; Donlin, Laura T.; Alexandropoulos, Konstantina

doi:10.1083/jcb1893oia8

Cited by 3 publications

(4 citation statements)

References 54 publications

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“…The diminished medulla and lack of K5 + mTECs also correlated with markedly reduced UEA + AIRE + mature mTECs (Supplemental Figure 2A). Quantitative analysis of mTEC subpopulations by flow cytometry showed drastically decreased production of immature and mature mTECs (Supplemental Figure 2B), previously described as UEA + MHCII int and UEA + MHCII hi , or intermediate and mature MHCII hi AIRE -and MHCII hi AIRE + cells (22)(23)(24). In contrast, cTECs identified as UEA -MHCII + cells were unaffected…”

Section: Tec-specific Deletion Of Traf6 Inhibits Mtec Developmentmentioning

confidence: 82%

“…Sorted CD4 + CD8 -CD25 -T cells (5 × 10 4 ) were cultured with irradiated splenocytes (5 × 10 4 ), stimulated with 1 μg/ml plate-bound anti-CD3ε (eBioscience), and labeled with CFSE (5 μM; Molecular Probes) in the presence or absence of CD4 + CD8 -mTEC purification. Thymi from Traf6ΔTEC and WT mice were dispersed, and single-epithelial cell suspensions were enriched using a Percoll gradient as described previously (24). TEC fractions were treated with anti-CD16/ CD32 blocking antibody (BD) and incubated with anti-CD45-PE ( AIH histopathology.…”

Section: Methodsmentioning

confidence: 99%

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Medullary thymic epithelial cell depletion leads to autoimmune hepatitis

Bonito

Aloman²,

Fiel³

et al. 2013

J. Clin. Invest.

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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.

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Section: Tec-specific Deletion Of Traf6 Inhibits Mtec Developmentmentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

Medullary thymic epithelial cell depletion leads to autoimmune hepatitis

Bonito

Aloman²,

Fiel³

et al. 2013

J. Clin. Invest.

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“…For example, increased mTEC numbers in mice, caused by either loss of TGF‐β‐mediated or OPG‐mediated negative control of medullary growth, was found to correlate with increased numbers of thymic Foxp3 + nTreg cells , while diminished mTEC numbers caused by a NIK mutation in aly/aly mice was shown to lead to reduced nTreg‐cell development . Interestingly, a partial reduction in mTECs observed in mice lacking the adapter molecule Sin did not alter numbers of Foxp3 + T cells in lymph nodes . Whether this reflects normal Foxp3 + T‐cell development in the presence of diminished mTEC numbers, or postthymic expansion of nTreg in peripheral tissues is not clear.…”

Section: Foxp3+ Natural Regulatory T Cellsmentioning

confidence: 99%

Thymus medulla fosters generation of natural Treg cells, invariant γδ T cells, and invariant NKT cells: What we learn from intrathymic migration

2015

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The organization of the thymus into distinct cortical and medullary regions enables it to control the step-wise migration and development of immature T-cell precursors. Such a process provides access to specialized cortical and medullary thymic epithelial cells at defined stages of maturation, ensuring the generation of self-tolerant and MHC-restricted conventional CD4+ and CD8+ αβ T cells. The migratory cues and stromal cell requirements that regulate the development of conventional αβ T cells have been well studied. However, the thymus also fosters the generation of several immunoregulatory T-cell populations that form key components of both innate and adaptive immune responses. These include Foxp3+ natural regulatory T cells, invariant γδ T cells, and CD1d-restricted invariant natural killer T cells (iNKT cells). While less is known about the intrathymic requirements of these nonconventional T cells, recent studies have highlighted the importance of the thymus medulla in their development. Here, we review recent findings on the mechanisms controlling the intrathymic migration of distinct T-cell subsets, and relate this to knowledge of the microenvironmental requirements of these cells.

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“…Sin is a signaling component that has recently been identified as another critical regulator of mTEC differentiation. Within the thymic stroma, it is expressed most highly in mTECs, and its absence in thymic stroma leads to their improper maturation and subsequent deficiencies in Aire expression and immune tolerance (64). The decreased immune tolerance in Sin −/− mice was suggested to result from defective negative selection by experiments using the OT‐II‐RIP‐mOVA model of Aire‐dependent negative selection.…”

Section: Thymocyte–mtec Interactions Are Required For Proper Mtec Matmentioning

confidence: 99%

Control of central and peripheral tolerance by Aire

Metzger

Anderson

2011

Immunological Reviews

149

111

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Summary The negative selection of self-reactive thymocytes depends on the induction of tissue-specific antigens by medullary thymic epithelial cells. The autoimmune regulator (Aire) protein plays an important role in turning on these antigens, and the absence of even one Aire-induced tissue-specific antigen in the thymus can lead to autoimmunity in the antigen-expressing target organ. Recently, Aire protein has been detected in peripheral lymphoid organs, suggesting that peripheral Aire plays a complementary role here. In these peripheral sites, Aire was found to regulate the expression of a group of tissue-specific antigens that is distinct from those expressed in the thymus. Furthermore, transgenic antigen expression in extrathymic Aire-expressing cells (eTACs) can mediate deletional tolerance, but the immunological relevance of Aire-dependent, endogenous tissue-specific antigens remains to be determined.

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Regulation of medullary thymic epithelial cell differentiation and function by the signaling protein Sin

Cited by 3 publications

References 54 publications

Medullary thymic epithelial cell depletion leads to autoimmune hepatitis

Medullary thymic epithelial cell depletion leads to autoimmune hepatitis

Thymus medulla fosters generation of natural Treg cells, invariant γδ T cells, and invariant NKT cells: What we learn from intrathymic migration

Control of central and peripheral tolerance by Aire

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