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 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 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.

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. 

Integrative analysis of scRNAs-seq and scATAC-seq revealed transit-amplifying thymic epithelial cells expressing autoimmune regulator

2021 ◽  
Author(s):  
Takahisa Miyao ◽  
Maki Miyauchi ◽  
S. Thomas Kelly ◽  
Tommy W. Terooatea ◽  
Tatsuya Ishikawa ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Single Cell ◽  
Tolerance Induction ◽  
Integrative Analysis ◽  
Thymic Epithelial Cells ◽  
Self Tolerance ◽  
Cell Assays ◽  
Medullary Thymic Epithelial Cells ◽  
Specific Antigens ◽  
Accessible Chromatin

SummaryMedullary thymic epithelial cells (mTECs) are critical for self-tolerance induction in T cells via promiscuous expression of tissue-specific antigens (TSAs), which are controlled by transcriptional regulator AIRE. Whereas AIRE-expressing (Aire+) mTECs undergo constant turnover in the adult thymus, mechanisms underlying differentiation of postnatal mTECs remain to be discovered. Integrative analysis of single-cell assays for transposase accessible chromatin (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) suggested the presence of proliferating mTECs with a specific chromatin structure, which express high levels of Aire and co-stimulatory molecules CD80 (Aire+CD80hi). Proliferating Aire+CD80hi mTECs detected by using Fucci technology express a minimal level of Aire-dependent TSAs and are converted into quiescent Aire+CD80hi mTECs expressing high levels of TSAs after a transit amplification. These data provide evidence for the existence of transit amplifying Aire+mTEC precursors during Aire+mTEC differentiation process of the postnatal thymus.

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 The transcriptional landscape of mTEChi and mTEClo.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Transcriptional Profiling ◽  
Cell Subset ◽  
Cell Types ◽  
Thymic Epithelial Cells ◽  
Surface Receptors ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Self Tolerance ◽  
Medullary Thymic Epithelial Cells ◽  
Differential Gene

Medullary thymic epithelial cells, or mTEC, are cells of the thymus that can be sorted and classified based on expression of the class II major histocompatibility complex, MHC-II (1-3). mTEChi and mTEClo can be further segregated by expression of the CD80 marker, but there are few systematic analyses of the unique transcriptional behavior of each mTEC cell subset (4-6). We performed global differential gene expression profiling by comparing the transcriptomes of mTEChi and mTEClo (7) to determine the most significant transcriptional differences between these two cell subsets of the thymus. We found nearly a dozen groups of gene that distinctly identify these two cell types from each other. These included phospholipase-type enzymes, transcription factors, transcriptional coactivators and epigenetic proteins, cell signaling intermediates, cell surface receptors, molecules involved in ubiquitination, taste receptors, cathepsins, and interleukin-13. mTEChi and mTEClo can be discerned with facility as discrete cell types independent of MHC-II and CD80 expression through systematic comparative transcriptional profiling and the molecular descriptions provided here can be used as a resource for future investigations into the organ primarily responsible for providing lymphocyte self-tolerance instruction.

scholarly journals Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development

2011 ◽  
Vol 208 (2) ◽  
pp. 383-394 ◽  
Author(s):  
Yu Lei ◽  
Adiratna Mat Ripen ◽  
Naozumi Ishimaru ◽  
Izumi Ohigashi ◽  
Takashi Nagasawa ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Chemokine Receptor ◽  
T Cell Development ◽  
Cell Development ◽  
Thymic Epithelial Cells ◽  
Naturally Occurring ◽  
Self Tolerance ◽  
Medullary Thymic Epithelial Cells ◽  
Deficient Mice

Dendritic cells (DCs) in the thymus (tDCs) are predominantly accumulated in the medulla and contribute to the establishment of self-tolerance. However, how the medullary accumulation of tDCs is regulated and involved in self-tolerance is unclear. We show that the chemokine receptor XCR1 is expressed by tDCs, whereas medullary thymic epithelial cells (mTECs) express the ligand XCL1. XCL1-deficient mice are defective in the medullary accumulation of tDCs and the thymic generation of naturally occurring regulatory T cells (nT reg cells). Thymocytes from XCL1-deficient mice elicit dacryoadenitis in nude mice. mTEC expression of XCL1, tDC medullary accumulation, and nT reg cell generation are diminished in Aire-deficient mice. These results indicate that the XCL1-mediated medullary accumulation of tDCs contributes to nT reg cell development and is regulated by Aire.

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
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