scholarly journals Sirt6 Regulates the Development of Medullary Thymic Epithelial Cells and Contributes to the Establishment of Central Immune Tolerance

2021 ◽  
Vol 9 ◽  
Author(s):  
Qian Zhang ◽  
Zhanfeng Liang ◽  
Jiayu Zhang ◽  
Tong Lei ◽  
Xue Dong ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Conditional Knockout ◽  
Thymic Epithelial Cells ◽  
Reduced Body ◽  
Epigenetic Regulator ◽  
Development And Differentiation ◽  
Medullary Thymic Epithelial Cells ◽  
Proliferation Ability ◽  
Made In

Although some advances have been made in understanding the molecular regulation of mTEC development, the role of epigenetic regulators in the development and maturation of mTEC is poorly understood. Here, using the TEC-specific Sirt6 knockout mice, we found the deacetylase Sirtuin 6 (Sirt6) is essential for the development of functionally competent mTECs. First of all, TEC-specific Sirt6 deletion dramatically reduces the mTEC compartment, which is caused by reduced DNA replication and subsequent impaired proliferation ability of Sirt6-deficient mTECs. Secondly, Sirt6 deficiency specifically accelerates the differentiation of mTECs from CD80–Aire– immature population to CD80+Aire– intermediate mature population by promoting the expression of Spib. Finally, Sirt6 ablation in TECs markedly interferes the proper expression of tissue-restricted antigens (TRAs) and impairs the development of thymocytes and nTreg cells. In addition, TEC conditional knockout of Sirt6 results in severe autoimmune disease manifested by reduced body weight, the infiltration of lymphocytes and the presence of autoantibodies. Collectively, this study reveals that the expression of epigenetic regulator Sirt6 in TECs is crucial for the development and differentiation of mTECs, which highlights the importance of Sirt6 in the establishment of central immune tolerance.

scholarly journals Resolution of primary hyperparathyroidism following surgical removal of cervical thymus

2017 ◽  
Vol 4 (2) ◽  
pp. 5
Author(s):  
Rossella Cannarella ◽  
Beniamino Scilletta ◽  
Roberto Scilletta ◽  
Gaetano Magro ◽  
Aldo E. Calogero
Keyword(s):  
Parathyroid Hormone ◽  
Primary Hyperparathyroidism ◽  
Single Case ◽  
Thymic Epithelial Cells ◽  
Surgical Removal ◽  
Thymus Tissue ◽  
Medullary Thymic Epithelial Cells ◽  
Serum Pth ◽  
Thymus Cells

Recent research has emphasized the capacity of thymus cells of producing parathyroid hormone (PTH) if adequately stimulated, and have investigated the role of the so-called “thymic PTH”, produced by the medullary thymic epithelial cells (m-TECs). To the best of our knowledge, only a single case of well-documented PTH secretion from a thymoma causing primary hyperparathyroidism (PHTP) has been reported in the literature so far. We report here the case of a female patient with PHTP who underwent neck exploration for a suspected parathyroid adenoma. After surgery, a normalization of serum PTH concentration was observed, but the histological examination of the surgically excised mass revealed exclusively normal thymus tissue. The present case provides additional evidence of PHTP caused by an ectopic thymus. 

Extrathymic Aire-expressing cells support maternal-fetal tolerance

2021 ◽  
Vol 6 (61) ◽  
pp. eabf1968
Author(s):  
Eva Gillis-Buck ◽  
Haleigh Miller ◽  
Marina Sirota ◽  
Stephan J. Sanders ◽  
Vasilis Ntranos ◽  
...  
Keyword(s):  
Thymic Epithelial Cells ◽  
Activated T Cells ◽  
Healthy Pregnancy ◽  
Follicular Helper ◽  
Immune Mediated ◽  
Self Tolerance ◽  
Selective Ablation ◽  
Medullary Thymic Epithelial Cells ◽  
Early Mouse

Healthy pregnancy requires tolerance to fetal alloantigens as well as syngeneic embryonic and placental antigens. Given the importance of the autoimmune regulator (Aire) gene in self-tolerance, we investigated the role of Aire-expressing cells in maternal-fetal tolerance. We report that maternal ablation of Aire-expressing (Aire+) cells during early mouse pregnancy caused intrauterine growth restriction (IUGR) in both allogeneic and syngeneic pregnancies. This phenotype is immune mediated, as IUGR was rescued in Rag1-deficient mice, and involved a memory response, demonstrated by recurrence of severe IUGR in second pregnancies. Single-cell RNA sequencing demonstrated that Aire+ cell depletion in pregnancy results in expansion of activated T cells, particularly T follicular helper cells. Unexpectedly, selective ablation of either Aire-expressing medullary thymic epithelial cells or extrathymic Aire-expressing cells (eTACs) mapped the IUGR phenotype exclusively to eTACs. Thus, we report a previously undescribed mechanism for the maintenance of maternal-fetal immune homeostasis and demonstrate that eTACs protect the conceptus from immune-mediated IUGR.

scholarly journals Hif-1α regulates differentiation of limb bud mesenchyme and joint development

2007 ◽  
Vol 177 (3) ◽  
pp. 451-464 ◽  
Author(s):  
Sylvain Provot ◽  
Dawn Zinyk ◽  
Yasemin Gunes ◽  
Richa Kathri ◽  
Quynh Le ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fetal Development ◽  
Adaptive Response ◽  
Conditional Knockout ◽  
Limb Bud ◽  
Low Oxygen ◽  
Joint Development ◽  
Low Oxygen Tension ◽  
Development And Differentiation

Recent evidence suggests that low oxygen tension (hypoxia) may control fetal development and differentiation. A crucial mediator of the adaptive response of cells to hypoxia is the transcription factor Hif-1α. In this study, we provide evidence that mesenchymal condensations that give origin to endochondral bones are hypoxic during fetal development, and we demonstrate that Hif-1α is expressed and transcriptionally active in limb bud mesenchyme and in mesenchymal condensations. To investigate the role of Hif-1α in mesenchymal condensations and in early chondrogenesis, we conditionally inactivated Hif-1α in limb bud mesenchyme using a Prx1 promoter-driven Cre transgenic mouse. Conditional knockout of Hif-1α in limb bud mesenchyme does not impair mesenchyme condensation, but alters the formation of the cartilaginous primordia. Late hypertrophic differentiation is also affected as a result of the delay in early chondrogenesis. In addition, mutant mice show a striking impairment of joint development. Our study demonstrates a crucial, and previously unrecognized, role of Hif-1α in early chondrogenesis and joint formation.

Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance

2010 ◽  
Vol 11 (6) ◽  
pp. 512-519 ◽  
Author(s):  
Maria Hinterberger ◽  
Martin Aichinger ◽  
Olivia Prazeres da Costa ◽  
David Voehringer ◽  
Reinhard Hoffmann ◽  
...  
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Cd4 T Cell ◽  
Thymic Epithelial Cells ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Medullary Thymic Epithelial Cells

scholarly journals Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels

2005 ◽  
Vol 202 (1) ◽  
pp. 33-45 ◽  
Author(s):  
Jens Derbinski ◽  
Jana Gäbler ◽  
Benedikt Brors ◽  
Sascha Tierling ◽  
Sunitha Jonnakuty ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Tolerance Induction ◽  
The Body ◽  
Thymic Epithelial Cells ◽  
Peripheral Tissues ◽  
Central Tolerance ◽  
Self Tolerance ◽  
Medullary Thymic Epithelial Cells ◽  
Thymic Stroma

The role of central tolerance induction has recently been revised after the discovery of promiscuous expression of tissue-restricted self-antigens in the thymus. The extent of tissue representation afforded by this mechanism and its cellular and molecular regulation are barely defined. Here we show that medullary thymic epithelial cells (mTECs) are specialized to express a highly diverse set of genes representing essentially all tissues of the body. Most, but not all, of these genes are induced in functionally mature CD80hi mTECs. Although the autoimmune regulator (Aire) is responsible for inducing a large portion of this gene pool, numerous tissue-restricted genes are also up-regulated in mature mTECs in the absence of Aire. Promiscuously expressed genes tend to colocalize in clusters in the genome. Analysis of a particular gene locus revealed expression of clustered genes to be contiguous within such a cluster and to encompass both Aire-dependent and –independent genes. A role for epigenetic regulation is furthermore implied by the selective loss of imprinting of the insulin-like growth factor 2 gene in mTECs. Our data document a remarkable cellular and molecular specialization of the thymic stroma in order to mimic the transcriptome of multiple peripheral tissues and, thus, maximize the scope of central self-tolerance.

scholarly journals LAMTOR2 Is Dispensable for T Cell Receptor-Mediated Signaling of Thymocytes but Controls Medullary Thymic Epithelial Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1122-1122
Author(s):  
Lina Wendeler ◽  
Lukas A Huber ◽  
Christoph Klein ◽  
Daniel Kotlarz
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
T Cell Development ◽  
Cell Development ◽  
Conditional Knockout ◽  
Poly I:C ◽  
Thymic Epithelial Cells

Abstract Human LAMTOR2 deficiency is characterized by severe congenital neutropenia, growth failure, partial albinism, as well as B and T cell deficiencies (Bohn et al., Nat Med 2007). To determine the role of the endosomal adaptor LAMTOR2 in T cell development and homeostasis we used conditional knockout mouse models. Mx1-Cre-driven knockout of Lamtor2 resulted in reduction of thymus weight and total thymocyte numbers. Immunophenotyping revealed an impaired T cell development characterized by a partial block at the double negative CD4-CD8- T cell precursor stage after 7 and 21 days of poly I:C injection that induced deletion of the Lamtor2 gene. Since Mx1-Cre-driven knockout does not allow a discrimination between T cell intrinsic and extrinsic effects, we next generated pre-TCRα-iCre conditional knockout mice. In contrast to Mx1-Cre-Lamtor2fl/fl mice, mice with T cell-specific knockout of Lamtor2 showed normal frequencies of total thymocytes and T cell progenitor subsets. Furthermore, LAMTOR2-deficient thymocytes exhibited normal TCR signaling (p-ERK, p-LAT, p-LCK, p-PLCγ, Nur77) and internalization of TCRβ upon stimulation with anti-CD3ε +/- anti-CD28, indicating that LAMTOR2 in T cells is dispensable for thymocyte development. To assess whether T cell developmental defects in Mx1-Cre-Lamtor2fl/fl mice are caused by a dysfunctional thymic epithelium, we analyzed thymic epithelial cells (TECs) after 4 days of poly I:C injection by flow cytometry and detected a reduced ratio of CD45-EpCAM+UEA-1+Ly51- medullary TECs (mTECs) to CD45-EpCAM+UEA-1-Ly51+ cortical TECs in LAMTOR2-deficient mice. Further studies are underway to determine the role of LAMTOR2 in mTECs. Taken together, our findings show that LAMTOR2 is not required for TCR-mediated signaling but plays a critical role in controlling mTEC homeostasis. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Role of Proteasomes in the Thymus

2021 ◽  
Vol 12 ◽  
Author(s):  
Melina Frantzeskakis ◽  
Yousuke Takahama ◽  
Izumi Ohigashi
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
T Cell Development ◽  
Thymic Epithelial Cells ◽  
Ubiquitinated Proteins ◽  
Self Tolerance ◽  
Essential Components ◽  
Medullary Thymic Epithelial Cells ◽  
Selection Of

The thymus provides a microenvironment that supports the generation and selection of T cells. Cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs) are essential components of the thymic microenvironment and present MHC-associated self-antigens to developing thymocytes for the generation of immunocompetent and self-tolerant T cells. Proteasomes are multicomponent protease complexes that degrade ubiquitinated proteins and produce peptides that are destined to be associated with MHC class I molecules. cTECs specifically express thymoproteasomes that are essential for optimal positive selection of CD8+ T cells, whereas mTECs, which contribute to the establishment of self-tolerance in T cells, express immunoproteasomes. Immunoproteasomes are also detectable in dendritic cells and developing thymocytes, additionally contributing to T cell development in the thymus. In this review, we summarize the functions of proteasomes expressed in the thymus, focusing on recent findings pertaining to the functions of the thymoproteasomes and the immunoproteasomes.

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