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.

scholarly journals Effect of Coxsackievirus B4 Infection on the Thymus: Elucidating Its Role in the Pathogenesis of Type 1 Diabetes

2021 ◽  
Vol 9 (6) ◽  
pp. 1177
Author(s):  
Abdulaziz Alhazmi ◽  
Magloire Pandoua Nekoua ◽  
Hélène Michaux ◽  
Famara Sane ◽  
Aymen Halouani ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Viral Infections ◽  
Lymphoid Organ ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Coxsackievirus B4

The thymus gland is a primary lymphoid organ for T-cell development. Various viral infections can result in disturbance of thymic functions. Medullary thymic epithelial cells (mTECs) are important for the negative selection of self-reactive T-cells to ensure central tolerance. Insulin-like growth factor 2 (IGF2) is the dominant self-peptide of the insulin family expressed in mTECs and plays a crucial role in the intra-thymic programing of central tolerance to insulin-secreting islet β-cells. Coxsackievirus B4 (CVB4) can infect and persist in the thymus of humans and mice, thus hampering the T-cell maturation and differentiation process. The modulation of IGF2 expression and protein synthesis during a CVB4 infection has been observed in vitro and in vivo in mouse models. The effect of CVB4 infections on human and mouse fetal thymus has been studied in vitro. Moreover, following the inoculation of CVB4 in pregnant mice, the thymic function in the fetus and offspring was disturbed. A defect in the intra-thymic expression of self-peptides by mTECs may be triggered by CVB4. The effects of viral infections, especially CVB4 infection, on thymic cells and functions and their possible role in the pathogenesis of type 1 diabetes (T1D) are presented.

scholarly journals Peyer's Patch Dendritic Cells Process Viral Antigen from Apoptotic Epithelial Cells in the Intestine of Reovirus-infected Mice

2004 ◽  
Vol 200 (2) ◽  
pp. 235-245 ◽  
Author(s):  
Marina N. Fleeton ◽  
Nikhat Contractor ◽  
Francisco Leon ◽  
J. Denise Wetzel ◽  
Terence S. Dermody ◽  
...  
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Cd4 T Cells ◽  
Cell Protein ◽  
Peyer’S Patch ◽  
Peyer's Patch ◽  
Antigen Uptake ◽  
Cross Presentation

We explored the role of Peyer's patch (PP) dendritic cell (DC) populations in the induction of immune responses to reovirus strain type 1 Lang (T1L). Immunofluorescence staining revealed the presence of T1L structural (σ1) and nonstructural (σNS) proteins in PPs of T1L-infected mice. Cells in the follicle-associated epithelium contained both σ1 and σNS, indicating productive viral replication. In contrast, σ1, but not σNS, was detected in the subepithelial dome (SED) in association with CD11c+/CD8α−/CD11blo DCs, suggesting antigen uptake by these DCs in the absence of infection. Consistent with this possibility, PP DCs purified from infected mice contained σ1, but not σNS, and PP DCs from uninfected mice could not be productively infected in vitro. Furthermore, σ1 protein in the SED was associated with fragmented DNA by terminal deoxy-UTP nick-end labeling staining, activated caspase-3, and the epithelial cell protein cytokeratin, suggesting that DCs capture T1L antigen from infected apoptotic epithelial cells. Finally, PP DCs from infected mice activated T1L-primed CD4+ T cells in vitro. These studies show that CD8α−/CD11blo DCs in the PP SED process T1L antigen from infected apoptotic epithelial cells for presentation to CD4+ T cells, and therefore demonstrate the cross-presentation of virally infected cells by DCs in vivo during a natural viral infection.

scholarly journals Role of Prolactin and Growth Hormone on Thymus Physiology

1998 ◽  
Vol 6 (3-4) ◽  
pp. 317-323 ◽  
Author(s):  
Valéria De Mello-Coelho ◽  
Wilson Savino ◽  
Marie-Catherine Postel-Vinay ◽  
Mireille Dardenne
Keyword(s):  
Growth Hormone ◽  
Epithelial Cells ◽  
Cell Types ◽  
Pituitary Hormones ◽  
Thymic Epithelial Cells ◽  
Double Positive ◽  
Gh Treatment ◽  
Thymic Hormone

Intrathymic T-cell differentiation is under the control of the thymic microenvironment, which acts on maturing thymocytes via membrane as well as soluble products. Increasing data show that this process can be modulated by classical hormones, as exemplified herein by prolactin (PRL) and growth hormone (GH), largely secreted by the pituitary gland.Both PRL and GH stimulate the secretion of thymulin, a thymic hormone produced by thymic epithelial cells. Conversely, low levels of circulating thymulin parallel hypopituitary states. Interestingly, the enhancing effects of GH on thymulin seem to be mediated by insulinlike growth factor (IGF-1) since they can be abrogated with anti-IGF-1 or anti-IGF-l-receptor antibodies. The influence of PRL and GH on the thymic epithelium is pleiotropic: PRL enhancesin vivothe expression of high-molecular-weight cytokeratins and stimulatesin vitroTEC proliferation, an effect that is shared by GH and IGF-1.Differentiating T cells are also targets for the intrathymic action of PRL and GH.In vivoinoculation of a rat pituitary cell line into old rats results in restoration of the thymus, including differentiation of CD4-CD8-thymocytes into CD4+CD8+cells. Furthermore, PRL may regulate the maintenance of thymocyte viability during the double-positive stage of thymocyte differentiation.Injections of GH into aging mice increase total thymocyte numbers and the percentage of CD3-bearing cells, as well as the Concanavalin-A mitogenic response and IL-6 production by thymocytes. Interestingly, similar findings are observed in animals treated with IGF-1. Lastly, the thymic hypoplasia observed in dwarf mice can be reversed with GH treatment.In keeping with the data summarized earlier is the detection of receptors for PRL and GH on both thymocytes and thymic epithelial cells. Importantly, recent studies indicate that both cell types can produce PRL and GH intrathymically. Similarly, production of IGF-1 and expression of a corresponding receptor has also been demonstrated.In conclusion, these data strongly indicate that the thymus is physiologically under control of pituitary hormones PRL and GH. In addition to the classical endocrine pathway, paracrine and autocrine circuits are probably implicated in such control.

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.

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.

p15Ink4b Maintains Normal Levels of Granulocyte-Macrophage Progenitors In Vivo.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2280-2280
Author(s):  
Michael Rosu-Myles ◽  
Linda Wolff
Keyword(s):  
Kinase Inhibitors ◽  
Flow Cytometric Analysis ◽  
Brdu Incorporation ◽  
Erythroid Progenitors ◽  
Hematopoietic Stem ◽  
Myeloid Progenitor ◽  
Proliferation And Differentiation ◽  
Stem And Progenitor Cells

Abstract Maintaining a balance between the proliferation and differentiation of hematopoietic stem and progenitor cells is crucial for normal maintenance of the hematopoietic system. The INK4 family of cyclin-dependent kinase inhibitors traditionally function in regulating cell proliferation by blocking G1/S phase transition during cell cycle. Loss of expression of one INK4 family member, p15INK4B, has been associated with acute myeloid leukemia (AML) and myelodysplasia and mice that lack p15Ink4b are more prone to developing retrovirus-induced AML. These data suggest an important role for p15INK4B in myeloid differentiation. Here we examined the hematopoietic progenitor pool in p15Ink4b deficient (Ink4b−/−) mice to determine its potential role in regulating hematopoietic precursors. In myeloid progenitor colony assays, bone marrow (BM) from Ink4b−/− mice were found to contain a 1.4 fold greater number of progenitors committed to the formation of granulocytes and macrophages (CFU-GM). This in vitro data was supported by flow cytometric analysis which determined that Ink4b−/− BM contained a 3-fold greater proportion of granulocyte-macrophage progenitors (GMP) (11+/−1.2% vs 34+/−9%) concomitant with a 2-fold decrease in common myeloid progenitors (CMP) (56+/−2 % vs 34+/−7 %). GMP isolated from Ink4b−/− BM also demonstrated a 3-fold greater propensity to form CFU-GM. Despite these differences, the proportion of cycling GMP or CMP in Ink4b−/− and wt mice were identical as determined by propidium iodide and Hoecsht dye DNA stains and in vivo BrdU incorporation. However, in response to specific cytokines, Ink4b−/− CMP showed an increased potential for GMP differentiation and a decreased capacity to form megakaryocyte-erythroid progenitors (MEP). Our work demonstrates that p15Ink4b functions in maintaining normal levels of CFU-GM and may regulate CMP differentiation in response to specific factors.

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 Autoimmune regulator act in synergism with thymocyte adhesion in the control of lncRNAs in medullary thymic epithelial cells

2021 ◽  
Author(s):  
Max J Duarte ◽  
Romario S Mascarenhas ◽  
Amanda F Assis ◽  
Pedro P Tanaka ◽  
Cesar A Speck-Hernandez ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Model Systems ◽  
Thymic Epithelial Cells ◽  
Large Set ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Autoimmune Regulator ◽  
Medullary Thymic Epithelial Cells

The autoimmune regulator (Aire) gene in medullary thymic epithelial cells (mTECs) encodes the AIRE protein, which interacts with its partners within the nucleus. This Aire complex induces stalled RNA Pol II on chromatin to proceed with transcription elongation of a large set of messenger RNAs and microRNAs. Considering that RNA Pol II also transcribes long noncoding RNAs (lncRNAs), we hypothesized that Aire might be implicated in the upstream control of this RNA species. To test this, we employed a loss-of-function approach in which Aire knockout mTECs were compared to Aire wild-type mTECs for lncRNA transcriptional profiling both in vitro and in vivo model systems. RNA sequencing enables the differential expression profiling of lncRNAs when these cells adhere in vitro to thymocytes or do not adhere to them as a way to test the effect of cell adhesion. Sets of lncRNAs that are unique and that are shared in vitro and in vivo were identified. Among these, we found the Aire-dependent lncRNAs as for example, Platr28, Ifi30, Morrbid, Malat1, and Xist. This finding represents the first evidence that Aire mediates the transcription of lncRNAs in mTECs. Microarray hybridizations enabled us to observe that temporal thymocyte adhesion modulates the expression levels of such lncRNAs as Morrbid, Xist, and Fbxl12o after 36h of adhesion. This finding shows the existence of a synergistic mechanism involving a link between thymocyte adhesion, Aire, and lncRNAs in mTECs that might be important for immune self-representation.

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