scholarly journals Thymic Medullary Epithelial Cell Differentiation, Thymocyte Emigration, and the Control of Autoimmunity Require Lympho–Epithelial Cross Talk via LTβR

2003 ◽  
Vol 198 (5) ◽  
pp. 757-769 ◽  
Author(s):  
Thomas Boehm ◽  
Stefanie Scheu ◽  
Klaus Pfeffer ◽  
Conrad C. Bleul
Keyword(s):  
Epithelial Cells ◽  
Cross Talk ◽  
Three Dimensional ◽  
Tolerance Induction ◽  
Nuclear Factor Κb ◽  
Thymic Epithelial Cells ◽  
Cell Repertoire ◽  
Central Tolerance ◽  
Signaling Axis ◽  
Normal Differentiation

Thymocytes depend on the interaction with thymic epithelial cells for the generation of a diverse, nonautoreactive T cell repertoire. In turn, thymic epithelial cells acquire their three-dimensional cellular organization via instructive signals from developing thymocytes. The nature of these signals has been elusive so far. We show that thymocytes and medullary epithelial cells (MECs) communicate via the lymphotoxin β receptor (LTβR) signaling axis. Normal differentiation of thymic MECs requires LTβR ligand on thymocytes and LTβR together with nuclear factor–κB-inducing kinase (Nik) in thymic epithelial cells. Impaired lympho–epithelial cross talk in the absence of the LTβR causes aberrant differentiation and reduced numbers of thymic MECs, leads to the retention of mature T lymphocytes, and is associated with autoimmune phenomena, suggesting an unexpected role for LTβR signaling in central tolerance induction.

scholarly journals Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire

2007 ◽  
Vol 204 (11) ◽  
pp. 2521-2528 ◽  
Author(s):  
Daniel Gray ◽  
Jakub Abramson ◽  
Christophe Benoist ◽  
Diane Mathis
Keyword(s):  
Epithelial Cells ◽  
Flow Cytometric Analysis ◽  
Tolerance Induction ◽  
Brdu Incorporation ◽  
Thymic Epithelial Cells ◽  
High Turnover ◽  
Central Tolerance ◽  
Cross Presentation

Expression of autoimmune regulator (Aire) by thymic medullary epithelial cells (MECs) is critical for central tolerance of self. To explore the mechanism by which such a rare cell population imposes tolerance on the large repertoire of differentiating thymocytes, we examined the proliferation and turnover of Aire+ and Aire− MEC subsets through flow cytometric analysis of 5-bromo-2′deoxyuridine (BrdU) incorporation. The Aire+ MEC subset was almost entirely postmitotic and derived from cycling Aire− precursors. Experiments using reaggregate thymic organ cultures revealed the presence of such precursors among Aire− MECs expressing low levels of major histocompatibility complex class II and CD80. The kinetics of BrdU decay showed the Aire+ population to have a high turnover. Aire did not have a direct impact on the division of MECs in vitro or in vivo but, rather, induced their apoptosis. We argue that these properties strongly favor a “terminal differentiation” model for Aire function in MECs, placing strict temporal limits on the operation of any individual Aire+ MEC in central tolerance induction. We further speculate that the speedy apoptosis of Aire-expressing MECs may be a mechanism to promote cross-presentation of the array of peripheral-tissue antigens they produce.

Epithelial cytoprotection sustains ectopic expression of tissue-restricted antigens in the thymus during murine acute GVHD

Blood ◽  
2013 ◽  
Vol 122 (5) ◽  
pp. 837-841 ◽  
Author(s):  
Simone Dertschnig ◽  
Gretel Nusspaumer ◽  
Robert Ivanek ◽  
Mathias M. Hauri-Hohl ◽  
Georg A. Holländer ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Ectopic Expression ◽  
Tolerance Induction ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Key Points

Key Points Acute GVHD predisposes to autoimmune chronic GVHD, but it is currently unclear how autoimmunity is linked to antecedent alloimmunity. Loss of central tolerance induction that occurs via functional compromise of thymic epithelial cells may provide such a pathogenic link.

scholarly journals Post-Aire Medullary Thymic Epithelial Cells and Hassall’s Corpuscles as Inducers of Tonic Pro-Inflammatory Microenvironment

2021 ◽  
Vol 12 ◽  
Author(s):  
Martti Laan ◽  
Ahto Salumets ◽  
Annabel Klein ◽  
Kerli Reintamm ◽  
Rudolf Bichele ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Tolerance Induction ◽  
Convincing Evidence ◽  
Keratinocyte Differentiation ◽  
Thymic Epithelial Cells ◽  
Special Focus ◽  
Central Tolerance ◽  
Inflammatory Microenvironment ◽  
Medullary Thymic Epithelial Cells ◽  
Late Stages

While there is convincing evidence on the role of Aire-positive medullary thymic epithelial cells (mTEC) in the induction of central tolerance, the nature and function of post-Aire mTECs and Hassall’s corpuscles have remained enigmatic. Here we summarize the existing data on these late stages of mTEC differentiation with special focus on their potential to contribute to central tolerance induction by triggering the unique pro-inflammatory microenvironment in the thymus. In order to complement the existing evidence that has been obtained from mouse models, we performed proteomic analysis on microdissected samples from human thymic medullary areas at different differentiation stages. The analysis confirms that at the post-Aire stages, the mTECs lose their nuclei but maintain machinery required for translation and exocytosis and also upregulate proteins specific to keratinocyte differentiation and cornification. In addition, at the late stages of differentiation, the human mTECs display a distinct pro-inflammatory signature, including upregulation of the potent endogenous TLR4 agonist S100A8/S100A9. Collectively, the study suggests a novel mechanism by which the post-Aire mTECs and Hassall’s corpuscles contribute to the thymic microenvironment with potential cues on the induction of central tolerance.

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 Thymus Medulla Formation and Central Tolerance Are Restored in IKKα−/− Mice That Express an IKKα Transgene in Keratin 5+ Thymic Epithelial Cells

2007 ◽  
Vol 178 (2) ◽  
pp. 829-837 ◽  
Author(s):  
Dakshayani Lomada ◽  
Bigang Liu ◽  
Lezlee Coghlan ◽  
Yinling Hu ◽  
Ellen R. Richie
Keyword(s):  
Epithelial Cells ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Keratin 5

scholarly journals Gene Modification and Three‐Dimensional Scaffolds as Novel Tools to Allow the Use of Postnatal Thymic Epithelial Cells for Thymus Regeneration Approaches

2019 ◽  
Vol 8 (10) ◽  
pp. 1107-1122 ◽  
Author(s):  
Ileana Bortolomai ◽  
Monica Sandri ◽  
Elena Draghici ◽  
Elena Fontana ◽  
Elisabetta Campodoni ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Three Dimensional ◽  
Thymic Epithelial Cells ◽  
Gene Modification ◽  
Thymus Regeneration

scholarly journals B7-CD28 co-stimulation modulates central tolerance via thymic clonal deletion and Treg generation through distinct mechanisms

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Masashi Watanabe ◽  
Ying Lu ◽  
Michael Breen ◽  
Richard J. Hodes
Keyword(s):  
Treg Cell ◽  
Specific Antigen ◽  
Cell Generation ◽  
Thymic Epithelial Cells ◽  
T Cell Repertoire ◽  
Cellular Mechanisms ◽  
Cell Repertoire ◽  
Clonal Deletion ◽  
Central Tolerance ◽  
Antigen Presenting

AbstractThe molecular and cellular mechanisms mediating thymic central tolerance and prevention of autoimmunity are not fully understood. Here we show that B7-CD28 co-stimulation and B7 expression by specific antigen-presenting cell (APC) types are required for clonal deletion and for regulatory T (Treg) cell generation from endogenous tissue-restricted antigen (TRA)-specific thymocytes. While B7-CD28 interaction is required for both clonal deletion and Treg induction, these two processes differ in their CD28 signaling requirements and in their dependence on B7-expressing dendritic cells, B cells, and thymic epithelial cells. Meanwhile, defective thymic clonal deletion due to altered B7-CD28 signaling results in the accumulation of mature, peripheral TRA-specific T cells capable of mediating destructive autoimmunity. Our findings thus reveal a function of B7-CD28 co-stimulation in shaping the T cell repertoire and limiting autoimmunity through both thymic clonal deletion and Treg cell generation.

scholarly journals The Aire family expands

2019 ◽  
Vol 216 (5) ◽  
pp. 1010-1011
Author(s):  
Adrian Liston ◽  
James Dooley
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Lymph Nodes ◽  
Thymic Epithelial Cells ◽  
T Cell Tolerance ◽  
T Cell Repertoire ◽  
Cell Tolerance ◽  
Cell Repertoire

T cell tolerance depends upon Aire-expressing cells to purge the T cell repertoire of autoreactive clones. Once thought to be the exclusive domain of thymic epithelial cells, a new study by Yamano et al. (https://doi.org/10.1084/jem.20181430) in this issue of JEM identifies ILC3-like cells in the lymph nodes with similar properties.

Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells

10.1038/71540 ◽  
2000 ◽  
Vol 6 (1) ◽  
pp. 56-61 ◽  
Author(s):  
Ludger Klein ◽  
Matthias Klugmann ◽  
Klaus-Armin Nave ◽  
V K Tuohy ◽  
Bruno Kyewski
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Splice Variant ◽  
Thymic Epithelial Cells ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Autoreactive T Cell
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