scholarly journals Thymus Inception: Molecular Network in the Early Stages of Thymus Organogenesis

2020 ◽  
Vol 21 (16) ◽  
pp. 5765
Author(s):  
Marta Figueiredo ◽  
Rita Zilhão ◽  
Hélia Neves
Keyword(s):  
Transcription Factor ◽  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Developmental Stages ◽  
Thymic Epithelial Cells ◽  
Environmental Cues ◽  
Special Focus ◽  
Thymic Epithelium ◽  
Stromal Microenvironment ◽  
Pharyngeal Endoderm

The thymus generates central immune tolerance by producing self-restricted and self-tolerant T-cells as a result of interactions between the developing thymocytes and the stromal microenvironment, mainly formed by the thymic epithelial cells. The thymic epithelium derives from the endoderm of the pharyngeal pouches, embryonic structures that rely on environmental cues from the surrounding mesenchyme for its development. Here, we review the most recent advances in our understanding of the molecular mechanisms involved in early thymic organogenesis at stages preceding the expression of the transcription factor Foxn1, the early marker of thymic epithelial cells identity. Foxn1-independent developmental stages, such as the specification of the pharyngeal endoderm, patterning of the pouches, and thymus fate commitment are discussed, with a special focus on epithelial–mesenchymal interactions.

scholarly journals Neuropeptides Exert Direct Effects on Rat Thymic Epithelial Cells in Culture

1998 ◽  
Vol 6 (1-2) ◽  
pp. 95-104 ◽  
Author(s):  
Gail M. Head ◽  
R. Mentlein ◽  
Birte Von Patay ◽  
J. E.G. Downing ◽  
Marion D. Kendall
Keyword(s):  
Epithelial Cells ◽  
Lucifer Yellow ◽  
Tritiated Thymidine ◽  
Single Cells ◽  
Thymic Epithelial Cells ◽  
Dye Coupling ◽  
Direct Effects ◽  
Adrenergic Agonist ◽  
Thymic Epithelium ◽  
Functional Aspects

To determine if major thymic neuropeptides and neurotransmitters can directly influence the functional activity of cultured rat thymic epithelium, neuropeptides and neurotransmitters were applied, and intercellular communication, proliferation, and thymulin secretion assessed. After injections of a mixture of lucifer yellow dextran (too large to pass gap junctions) and cascade blue (which does) into single cells, some neuropeptides decrease dye coupling: 0.1 mM GABA (P< 0.0001), 100 nM NPY (P< 0.0001), 100 nM VIP (P< 0.001), 100 nM CGRP (P< 0.001), 100 nM SP (P< 0.01), and 0.1 mM histamine (P< 0.01), whereas 0.1 mM 5-HT, mM acetylcholine, and 1μM isoproterenol (β-adrenergic agonist) had no effect. Proliferation (incorporation of tritiated thymidine) was increased by CGRP (P= 0.004) and histamine (P< 0.02), but decreased by isoproterenol (P= 0.002), 5-HT (P= 0.003), and acetylcholine (P< 0.05). The percentage of multinucleate cells was decreased after isoproterenol (2.5%), and increased after 5-HT (21.3%), GABA (15%), and histamine (15.1%). Compared to controls, thymulin in the supernatant was decreased after challenge with acetylcholine (52%), isoproterenol (71%), 5-HT (73%), and histamine (84%). This study demonstrates direct effects of neuropeptides and neurotransmitters on functional aspects of cultured thymic epithelial cells.

Lineage potential, plasticity and environmental reprogramming of epithelial stem/progenitor cells

2014 ◽  
Vol 42 (3) ◽  
pp. 637-644 ◽  
Author(s):  
Alessandro W. Amici ◽  
Fatai O. Onikoyi ◽  
Paola Bonfanti
Keyword(s):  
Stem Cells ◽  
Epithelial Cells ◽  
Cell Therapy ◽  
Hair Follicle ◽  
Progenitor Cells ◽  
Environmental Cues ◽  
Full Potential ◽  
Thymic Epithelium ◽  
Differentiated Cells ◽  
Stratified Epithelia

Recent evidence supports and reinforces the concept that environmental cues may reprogramme somatic cells and change their natural fate. In the present review, we concentrate on environmental reprogramming and fate potency of different epithelial cells. These include stratified epithelia, such as the epidermis, hair follicle, cornea and oesophagus, as well as the thymic epithelium, which stands alone among simple and stratified epithelia, and has been shown recently to contain stem cells. In addition, we briefly discuss the pancreas as an example of plasticity of intrinsic progenitors and even differentiated cells. Of relevance, examples of plasticity and fate change characterize pathologies such as oesophageal metaplasia, whose possible cell origin is still debated, but has important implications as a pre-neoplastic event. Although much work remains to be done in order to unravel the full potential and plasticity of epithelial cells, exploitation of this phenomenon has already entered the clinical arena, and might provide new avenues for future cell therapy of these tissues.

scholarly journals Heterogeneity of thymic epithelial cell (TEC) keratins--immunohistochemical and biochemical evidence for a subset of highly differentiated TEC in the mouse.

1985 ◽  
Vol 33 (7) ◽  
pp. 687-694 ◽  
Author(s):  
J F Nicolas ◽  
W Savino ◽  
A Reano ◽  
J Viac ◽  
J Brochier ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
High Molecular Weight ◽  
Thymic Epithelial Cells ◽  
Thymic Epithelial Cell ◽  
Small Subset ◽  
Thymic Epithelium ◽  
Differentiated Cells ◽  
Medullary Epithelial Cells

The mouse thymic epithelial network was studied using three different anti-keratin antibodies. One of these antibodies, KL1, exclusively recognized a small subset of medullary epithelial cells characterized by its content of a high molecular weight keratin (63 kD). Since epithelial differentiation is known to be associated with the acquisition of high molecular weight keratins, KL1-positive cells, which express the Ia antigen and secrete thymulin, may represent a subset of highly differentiated cells among mouse thymic epithelial cells (TEC). These data reflect the heterogeneity of the thymic epithelium and support the concept that distinct TEC subsets might provide the thymus with different microenvironments.

scholarly journals Specific Inhibition of Interferon Signal Transduction Pathways by Adenoviral Infection

2001 ◽  
Vol 276 (50) ◽  
pp. 47136-47142 ◽  
Author(s):  
Theresa D. Joseph ◽  
Dwight C. Look
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Transcription Factor ◽  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Airway Epithelial Cells ◽  
Signal Transducer ◽  
Airway Epithelial ◽  
Complex Assembly ◽  
Ifn Γ

Adenoviral evolution has generated strategies to resist host cell antiviral systems, but molecular mechanisms for evasion of interferon (IFN) effects by adenoviruses during late-phase infection are poorly defined. In this study, we examined adenovirus type 5 (AdV) effects on IFN-γ-dependent gene expression and Janus family kinase-signal transducer and activator of transcription signaling components in human tracheobronchial epithelial cells. We found that AdV infection specifically inhibited IFN-γ-dependent gene expression in airway epithelial cells without evidence of epithelial cell injury or generation of a soluble extracellular inhibitor. Furthermore, infection with AdV for 18–24 h blocked phosphorylation/activation of the Stat1 transcription factor that regulates IFN-γ-dependent genes. Although AdV also inhibited IFN-α-dependent phosphorylation of Stat1 and Stat2, interleukin-4-dependent phosphorylation of the related transcription factor Stat6 was not affected, indicating that the virus selectively affected specific signaling pathways. Our results indicate that AdV inhibition of the IFN-γ signal transduction cascade occurs through loss of ligand-induced receptor complex assembly and consequent component phosphorylation and suggest that lack of complex assembly is due to decreased expression of the IFN-γR2 chain of the IFN-γ receptor. IFN-γR2 is required at an early step in Janus family kinase-signal transducer and activator of transcription pathway activation and is expressed at low levels in airway epithelial cells, supporting the concept that adenoviral down-regulation of the level of this IFN-γ receptor component allows for persistent modulation of IFN-γ-dependent gene expression.

From the Bone Marrow to the Thymic Niche

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5123-5123
Author(s):  
Sandrine Susini ◽  
Séverine Mouraud ◽  
Elodie Elkaim ◽  
Julien Roullier ◽  
Sonia Luce ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Epithelial Cells ◽  
Progenitor Cells ◽  
Chemokine Receptors ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Adult Life ◽  
Thymic Epithelial Cells

Abstract To generate T cells throughout adult life, the thymus must import hematopoietic progenitor cells from the bone marrow via the blood. The cellular and molecular mechanisms governing the circulation of thymus-seeding progenitor cells are well characterized in mice but not in humans. The aim of the present study was to characterize the molecular mechanisms and cellular components involved in thymus colonization by lymphoid progenitors (CD34+/CD10+/CD7-/CD24-) and the early steps of thymopoiesis under physiological conditions in humans. Our results demonstrate that circulating lymphoid progenitor cells express CCR9 and CXCR4 chemokine receptors, VLA-4, VLA-5 and VLA-6 integrins and PSGL-1 and CD44 adhesion molecules. We used in vitro migration and adhesion assays to validate the functional status of these markers. As in the mouse, human circulating progenitor cells enter the thymus at the corticomedullary junction (CMJ). Once in the thymus, crosstalk with thymic epithelial cells causes the circulating progenitors to commit to the T-cell differentiation pathway. In order to characterize thymic niches and interactions between circulating progenitors and the thymic stroma, we undertook a chemokine/chemokine-receptor-focused gene expression analysis of sorted lymphoid progenitor cells and CMJ epithelial cells (based on the expression of EpCAM and Delta-like-4). We observed an unexpected gene expression profile for chemokines and chemokine regulators in thymus-seeding CD34+/CD10+/CD7-/CD24- cells and epithelial cells at the CMJ. The present results should help us to highlight candidate genes involved in the early steps of human thymopoiesis. Disclosures No relevant conflicts of interest to declare.

scholarly journals RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla

2007 ◽  
Vol 204 (6) ◽  
pp. 1267-1272 ◽  
Author(s):  
Simona W. Rossi ◽  
Mi-Yeon Kim ◽  
Andreas Leibbrandt ◽  
Sonia M. Parnell ◽  
William E. Jenkinson ◽  
...  
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Cell Receptor ◽  
Thymic Epithelial Cells ◽  
Receptor Repertoire ◽  
Thymic Medulla ◽  
Medullary Thymic Epithelial Cells ◽  
Functional Regulation ◽  
Lymphoid Structures

Aire-expressing medullary thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptor repertoire of self-reactive specificities. Here we demonstrate a novel role for a CD4+3− inducer cell population, previously linked to development of organized secondary lymphoid structures and maintenance of T cell memory in the functional regulation of Aire-mediated promiscuous gene expression in the thymus. CD4+3− cells are closely associated with mTECs in adult thymus, and in fetal thymus their appearance is temporally linked with the appearance of Aire+ mTECs. We show that RANKL signals from this cell promote the maturation of RANK-expressing CD80−Aire− mTEC progenitors into CD80+Aire+ mTECs, and that transplantation of RANK-deficient thymic stroma into immunodeficient hosts induces autoimmunity. Collectively, our data reveal cellular and molecular mechanisms leading to the generation of Aire+ mTECs and highlight a previously unrecognized role for CD4+3−RANKL+ inducer cells in intrathymic self-tolerance.

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 Circulating mature dendritic cells homing to the thymus promote thymic epithelial cells involution via the Jagged1/Notch3 axis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Haojie Wu ◽  
Xiaohan Li ◽  
Chen Zhou ◽  
Qihong Yu ◽  
Shiyao Ge ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Transplant Rejection ◽  
Adaptive Immune Response ◽  
Thymic Epithelial Cells ◽  
Inflammatory Conditions ◽  
Mass Migration ◽  
Short Period ◽  
Intrathymic Injection

AbstractMultiple proinflammatory conditions, including chemotherapy, radiotherapy, transplant rejection, and microbial infections, have been identified to induce involution of the thymus. However, the underlying cellular and molecular mechanisms of these inflammatory conditions inducing apoptosis of thymic epithelial cells (TECs), the main components of the thymus, remain largely unknown. In the circulation, mature dendritic cells (mDCs), the predominant initiator of innate and adaptive immune response, can migrate into the thymus. Herein, we demonstrated that mDCs were able to directly inhibit TECs proliferation and induce their apoptosis by activating the Jagged1/Notch3 signaling pathway. Intrathymic injection of either mDCs or recombinant mouse Jagged1-human Fc fusion protein (rmJagged1-hFc) into mice resulted in acute atrophy of the thymus. Furthermore, DAPT, a γ-secretase inhibitor, reversed the effects induced by mDC or rmJagged1-hFc. These findings suggest that acute or aging-related thymus degeneration can be induced either by mass migration of circulating mDCs in a short period of time or by a few but constantly homing mDCs.

scholarly journals Contrasting models of promiscuous gene expression by thymic epithelium

2005 ◽  
Vol 202 (1) ◽  
pp. 15-19 ◽  
Author(s):  
Geoffrey O. Gillard ◽  
Andrew G. Farr
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Broad Spectrum ◽  
Alternative Model ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Thymic Epithelium ◽  
Medullary Thymic Epithelial Cells ◽  
Promiscuous Gene Expression ◽  
Self Antigens

Medullary thymic epithelial cells (mTECs) express a broad spectrum of tissue- restricted self-antigens (TRAs), which are required for the development of central tolerance. A new study suggests that TRA expression is a specialized property of terminally differentiated mTECs. However, as discussed here, an alternative model—whereby TRA expression is regulated by conserved developmental programs active in developing mTECs—may be equally plausible.

scholarly journals Ontogeny of Rat Thymic Epithelium Defined by Monoclonal Anticytokeratin Antibodies

1990 ◽  
Vol 1 (2) ◽  
pp. 67-75 ◽  
Author(s):  
Miodrag Čolić ◽  
Suzana Jovanović ◽  
Milijana Vasiljevski ◽  
Aleksandar Dujić
Keyword(s):  
Monoclonal Antibodies ◽  
Epithelial Cells ◽  
Thymic Epithelial Cells ◽  
Postnatal Life ◽  
Immunoperoxidase Method ◽  
Simultaneous Presence ◽  
Thymic Epithelium ◽  
Large Panel ◽  
Ontogenetic Study

Ontogenetic study on the expression of cytokeratin (CK) polypeptides within particular subsets of rat thymic epithelial cells (TEC) has been performed by a large panel of anti-CK monoclonal antibodies (mAbs) using the streptavidin-biotin immunoperoxidase method. Simultaneous presence of two or more CK subunits in the same TEC has been demonstrated by double immunoflouorescence labeling. The obtained results showed that the expression of CK polypeptides in fetal and neonatal thymus differed from the adult patterns. The main difference was observed in expression of CK10, 18, and 19 polypeptides. During fetal ontogeny, CK10 and 18 are markers for most medullary TEC or a subset of medullary TEC, respectively, whereas CK19 is mainly a pan-TEC marker. In the adult animals, they are localized in the cortical and a subset of medullary TEC (CK18), subcapsular/perivascular and some medullary TEC (CK19), or in a subset of medullary TEC and Hasall’s corpuscles (HC) (CK10). The switch in their expression in the cortex was observed during the first two weeks of postnatal life.

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