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 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.

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.

Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells

2007 ◽  
Vol 8 (4) ◽  
pp. 351-358 ◽  
Author(s):  
Katharina Aschenbrenner ◽  
Louise M D'Cruz ◽  
Elisabeth H Vollmann ◽  
Maria Hinterberger ◽  
Jan Emmerich ◽  
...  
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Regulatory T Cells ◽  
Thymic Epithelial Cells ◽  
Medullary Thymic Epithelial Cells ◽  
Self Antigen ◽  
Selection Of

scholarly journals Fine-tuning of β-catenin in thymic epithelial cells is required for postnatal T cell development

2021 ◽  
Author(s):  
Sayumi Fujimori ◽  
Izumi Ohigashi ◽  
Hayato Abe ◽  
M Mark Taketo ◽  
Yousuke Takahama ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cells ◽  
T Cell Development ◽  
Cell Development ◽  
Fine Tuning ◽  
Thymic Epithelial Cells ◽  
Loss Of Function ◽  
Thymic Epithelium

In the thymus, the thymic epithelium provides a microenvironment essential for the development of functionally competent and self-tolerant T cells. Previous findings showed that modulation of Wnt/β-catenin signaling in thymic epithelial cells (TECs) disrupts embryonic thymus organogenesis. However, the role of β-catenin in TECs for postnatal T cell development remains to be elucidated. Here, we analyzed gain-of function (GOF) and loss-of-function (LOF) of β-catenin highly specific in TECs. We found that GOF of β-catenin in TECs results in severe thymic dysplasia and T cell deficiency beginning from the embryonic period. By contrast, LOF of β-catenin in TECs reduces the number of cortical TECs and thymocytes modestly and only postnatally. These results indicate that fine-tuning of β-catenin expression within a permissive range is required for TECs to generate an optimal microenvironment to support postnatal T cell development.

scholarly journals In Pursuit of Adult Progenitors of Thymic Epithelial Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Tatsuya Ishikawa ◽  
Nobuko Akiyama ◽  
Taishin Akiyama
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Adaptive Immune System ◽  
Thymic Epithelial Cells ◽  
Adaptive Immune ◽  
Peripheral T Cells ◽  
Robust Adaptive ◽  
Adult Thymus ◽  
Shed Light ◽  
Selection Of

Peripheral T cells capable of discriminating between self and non-self antigens are major components of a robust adaptive immune system. The development of self-tolerant T cells is orchestrated by thymic epithelial cells (TECs), which are localized in the thymic cortex (cortical TECs, cTECs) and medulla (medullary TECs, mTECs). cTECs and mTECs are essential for differentiation, proliferation, and positive and negative selection of thymocytes. Recent advances in single-cell RNA-sequencing technology have revealed a previously unknown degree of TEC heterogeneity, but we still lack a clear picture of the identity of TEC progenitors in the adult thymus. In this review, we describe both earlier and recent findings that shed light on features of these elusive adult progenitors in the context of tissue homeostasis, as well as recovery from stress-induced thymic atrophy.

scholarly journals The Early Postnatal Life: A Dynamic Period in Thymic Epithelial Cell Differentiation

2021 ◽  
Vol 12 ◽  
Author(s):  
Ruben G. R. Pinheiro ◽  
Nuno L. Alves
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cell ◽  
T Cell Development ◽  
Thymic Epithelial Cells ◽  
Thymic Epithelial Cell ◽  
Postnatal Life ◽  
Functionally Diverse ◽  
Redundant Role

The microenvironments formed by cortical (c) and medullary (m) thymic epithelial cells (TECs) play a non-redundant role in the generation of functionally diverse and self-tolerant T cells. The role of TECs during the first weeks of the murine postnatal life is particularly challenging due to the significant augment in T cell production. Here, we critically review recent studies centered on the timely coordination between the expansion and maturation of TECs during this period and their specialized role in T cell development and selection. We further discuss how aging impacts on the pool of TEC progenitors and maintenance of functionally thymic epithelial microenvironments, and the implications of these chances in the capacity of the thymus to sustain regular thymopoiesis throughout life.

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