scholarly journals A model of preferential pairing between epithelial and dendritic cells in thymic antigen transfer

2021 ◽  
Author(s):  
Dominik Filipp ◽  
Richard S Blumberg ◽  
Matouš Vobořil ◽  
Jiří Březina ◽  
Tomáš Brabec ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Fluorescent Proteins ◽  
Thymic Epithelial Cells ◽  
Preferential Pairing ◽  
Central Tolerance ◽  
Specific Subset ◽  
Antigen Transfer ◽  
Medullary Thymic Epithelial Cells ◽  
T Cell Selection ◽  
Self Antigens

Medullary thymic epithelial cells (mTECs) which produce and present self-antigens are essential for the establishment of central tolerance. Since mTEC numbers are limited, their function is complemented by thymic dendritic cells (DCs), which transfer mTEC-produced self-antigens via cooperative antigen transfer (CAT). While CAT is required for effective T cell selection, many aspects remain enigmatic. Given the recently described heterogeneity of mTECs and DCs, it is unclear whether the antigen acquisition from a particular TEC subset is mediated by preferential pairing with specific subset of DCs. Using several relevant Cre-based mouse models controlling the expression of fluorescent proteins, we found that in regards to CAT, each subset of thymic DCs preferentially targets distinct mTEC subset(s) and importantly, XCR1+ activated DCs represented the most potent subset in CAT. Interestingly, one thymic DC can acquire antigen repetitively and of these, monocyte-derived DCs (moDC) were determined to be the most efficient in repetitive CAT. moDCs also represented the most potent DC subset in the acquisition of antigen from other DCs. These findings suggest a preferential pairing model for the distribution of mTEC-derived antigens among distinct populations of thymic DCs.

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 The thymic medulla: a unique microenvironment for intercellular self-antigen transfer

2009 ◽  
Vol 206 (7) ◽  
pp. 1505-1513 ◽  
Author(s):  
Christian Koble ◽  
Bruno Kyewski
Keyword(s):  
Ex Vivo ◽  
Cell Lineage ◽  
Tolerance Induction ◽  
Antigen Expression ◽  
Thymic Epithelial Cells ◽  
T Regulatory Cell ◽  
Central Tolerance ◽  
Medullary Thymic Epithelial Cells ◽  
Self Antigen ◽  
Self Antigens

Central tolerance is shaped by the array of self-antigens expressed and presented by various types of thymic antigen-presenting cells (APCs). Depending on the overall signal quality and/or quantity delivered in these interactions, self-reactive thymocytes either apoptose or commit to the T regulatory cell lineage. The cellular and molecular complexity underlying these events has only recently been appreciated. We analyzed the ex vivo presentation of ubiquitous or tissue-restricted self-antigens by medullary thymic epithelial cells (mTECs) and thymic dendritic cells (DCs), the two major APC types present in the medulla. We found that the ubiquitously expressed nuclear neo–self-antigen ovalbumin (OVA) was efficiently presented via major histocompatibility complex class II by mTECs and thymic DCs. However, presentation by DCs was highly dependent on antigen expression by TECs, and hemopoietic cells did not substitute for this antigen source. Accordingly, efficient deletion of OVA-specific T cells correlated with OVA expression by TECs. Notably, OVA was only presented by thymic but not peripheral DCs. We further demonstrate that thymic DCs are constitutively provided in situ with cytosolic as well as membrane-bound mTEC-derived proteins. The subset of DCs displaying transferred proteins was enriched in activated DCs, with these cells being most efficient in presenting TEC-derived antigens. These data provide evidence for a unique, constitutive, and unidirectional transfer of self-antigens within the thymic microenvironment, thus broadening the cellular base for tolerance induction toward promiscuously expressed tissue antigens.

scholarly journals Selective involution of thymic medulla by cyclosporine A with a decrease of mature thymic epithelia, XCR1+ dendritic cells, and epithelium-free areas containing Foxp3+ thymic regulatory T cells

2021 ◽  
Author(s):  
Yasushi Sawanobori ◽  
Yusuke Kitazawa ◽  
Hisashi Ueta ◽  
Kenjiro Matsuno ◽  
Nobuko Tokuda
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cyclosporine A ◽  
Immunosuppressive Drugs ◽  
Cell System ◽  
Thymic Epithelial Cells ◽  
Complex Molecules ◽  
Single Positive ◽  
Thymic Medulla ◽  
Medullary Thymic Epithelial Cells

AbstractImmunosuppressive drugs such as cyclosporine A (CSA) can disrupt thymic structure and functions, ultimately inducing syngeneic/autologous graft-versus-host disease together with involuted medullas. To elucidate the effects of CSA on the thymus more precisely, we analyzed the effects of CSA on the thymus and T cell system using rats. In addition to confirming the phenomena already reported, we newly found that the proportion of recent thymic emigrants also greatly decreased, suggesting impaired supply. Immunohistologically, the medullary thymic epithelial cells (mTECs) presented with a relative decrease in the subset with a competent phenotype and downregulation of class II major histocompatibility complex molecules. In control rats, thymic dendritic cells (DCs) comprised two subsets, XCR1+SIRP1α−CD4− and XCR1−SIRP1α+CD4+. The former had a tendency to selectively localize in the previously-reported epithelium-containing areas of the rat medullas, and the number was significantly reduced by CSA treatment. The epithelium-free areas, another unique domains in the rat medullas, contained significantly more Foxp3+ thymic Tregs. With CSA treatment, the epithelium-free areas presented strong involution, and the number and distribution of Tregs in the medulla were greatly reduced. These results suggest that CSA inhibits the production of single-positive thymocytes, including Tregs, and disturbs the microenvironment of the thymic medulla, with a decrease of the competent mTECs and disorganization of epithelium-free areas and DC subsets, leading to a generation of autoreactive T cells with selective medullary involution.

scholarly journals Dendritic cell sphingosine-1-phosphate lyase regulates thymic egress

2016 ◽  
Vol 213 (12) ◽  
pp. 2773-2791 ◽  
Author(s):  
Jesus Zamora-Pineda ◽  
Ashok Kumar ◽  
Jung H. Suh ◽  
Meng Zhang ◽  
Julie D. Saba
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Stromal Cells ◽  
Thymic Epithelial Cells ◽  
Homeostatic Regulation ◽  
Wild Type ◽  
Central Tolerance ◽  
Corticomedullary Junction ◽  
Sphingosine 1 Phosphate ◽  
S1p Lyase

T cell egress from the thymus is essential for adaptive immunity and involves chemotaxis along a sphingosine-1-phosphate (S1P) gradient. Pericytes at the corticomedullary junction produce the S1P egress signal, whereas thymic parenchymal S1P levels are kept low through S1P lyase (SPL)–mediated metabolism. Although SPL is robustly expressed in thymic epithelial cells (TECs), in this study, we show that deleting SPL in CD11c+ dendritic cells (DCs), rather than TECs or other stromal cells, disrupts the S1P gradient, preventing egress. Adoptive transfer of peripheral wild-type DCs rescued the egress phenotype of DC-specific SPL knockout mice. These studies identify DCs as metabolic gatekeepers of thymic egress. Combined with their role as mediators of central tolerance, DCs are thus poised to provide homeostatic regulation of thymic export.

scholarly journals Expression of the Autoimmune Regulator Gene and Its Relevance to the Mechanisms of Central and Peripheral Tolerance

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Roberto Perniola
Keyword(s):  
Peripheral Tolerance ◽  
Thymic Epithelial Cells ◽  
Monogenic Disease ◽  
Central Tolerance ◽  
Autoimmune Regulator ◽  
Pathogenic Variants ◽  
Autoimmune Polyendocrine Syndrome ◽  
Murine Homolog ◽  
Genes Encoding ◽  
Medullary Thymic Epithelial Cells

The autoimmune polyendocrine syndrome type 1 (APS-1) is a monogenic disease due to pathogenic variants occurring in the autoimmune regulator (AIRE) gene. Its related protein, AIRE, activates the transcription of genes encoding for tissue-specific antigens (TsAgs) in a subset of medullary thymic epithelial cells: the presentation of TsAgs to the maturating thymocytes induces the apoptosis of the autoreactive clones and constitutes the main form of central tolerance. Dysregulation of thymicAIREexpression in genetically transmitted and acquired diseases other than APS-1 may contribute to further forms of autoimmunity. AsAIREand its murine homolog are also expressed in the secondary lymphoid organs, the extent and relevance of AIRE participation in the mechanisms of peripheral tolerance need to be thoroughly defined.

Autonomous versus dendritic cell-dependent contributions of medullary thymic epithelial cells to central tolerance

2011 ◽  
Vol 32 (5) ◽  
pp. 188-193 ◽  
Author(s):  
Ludger Klein ◽  
Maria Hinterberger ◽  
Julia von Rohrscheidt ◽  
Martin Aichinger
Keyword(s):  
Dendritic Cell ◽  
Epithelial Cells ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Medullary Thymic Epithelial Cells

scholarly journals Aire-dependent transcripts escape H3K36me3 and Raver2 induced alternative splicing to sustain central immune tolerance

2021 ◽  
Author(s):  
Francine Padonou ◽  
Virginie Gonzalez ◽  
Nada Jmari ◽  
Julia Maslovskaja ◽  
Kai Kisand ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Negative Selection ◽  
Thymic Epithelial Cells ◽  
Related Factor ◽  
Splice Isoforms ◽  
Peripheral Tissues ◽  
Central Tolerance ◽  
Medullary Thymic Epithelial Cells ◽  
Self Antigen ◽  
High Diversity

AbstractAire allows medullary thymic epithelial cells (mTECs) to express and present a large number of self-antigens for central tolerance. Although mTECs express a high diversity of self-antigen splice isoforms, the extent and regulation of alternative splicing events (ASEs) included in their transcripts, notably in those induced by Aire, is unknown. Unexpectedly, and in contrast to Aire-neutral genes, we found that the Aire-sensitive genes exhibit in Aire-positive and negative mTECs, a weak inclusion of ASEs, with about a quarter present in peripheral tissues being excluded from the thymus. We identified Raver2, as a splicing-related factor overrepresented in mTECs and dependent on H3K36me3 marks. We discovered that both Raver2 and methylation of H3K36 promoted ASE inclusion for Aire-neutral genes, leaving Aire-sensitive genes unaffected. Profiling of H3K36me3 revealed its depletion at Aire-sensitive genes, supporting a mechanism, whose setup precedes Aire’s expression and by which Aire-sensitive genes exhibit weak ASE inclusion through the escape of Raver2’s effect. Lack of ASEs in Aire-induced transcripts highlights a role for regulatory T cells in controlling the incomplete Aire-dependent negative selection.

scholarly journals Immunohistological Analysis of the Jun Family and the Signal Transducers and Activators of Transcription in Thymus

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Alexandra Papoudou-Bai ◽  
Alexandra Barbouti ◽  
Vassiliki Galani ◽  
Kalliopi Stefanaki ◽  
Panagiotis Kanavaros
Keyword(s):  
Dendritic Cells ◽  
Epithelial Cells ◽  
Thymic Epithelial Cells ◽  
Double Immunostaining ◽  
Signal Transducers ◽  
Expression Levels ◽  
Proliferation And Apoptosis ◽  
Medullary Thymic Epithelial Cells ◽  
Immunohistological Analysis ◽  
Signal Transducers And Activators

The Jun family and the signal transducers and activators of transcription (STAT) are involved in proliferation and apoptosis. Moreover, c-Jun and STAT3 cooperate to regulate apoptosis. Therefore, we used double immunostaining to investigate the immunotopographical distribution of phospho-c-Jun (p-c-Jun), JunB, JunD, p-STAT3, p-STAT5, and p-STAT6 in human thymus. JunD was frequently expressed by thymocytes with higher expression in medullary compared to cortical thymocytes. p-c-Jun was frequently expressed by cortical and medullary thymic epithelial cells (TEC) and Hassall bodies (HB). p-STAT3 was frequently expressed by TEC with higher expression in cortical compared to medullary TEC and HB. p-c-Jun, JunB, p-STAT3, p-STAT5, and p-STAT6 were rarely expressed by thymocytes. JunB and JunD were expressed by rare cortical TEC with higher expression in medullary TEC. p-STAT5 and p-STAT6 were expressed by rare cortical and medullary TEC. Double immunostaining revealed p-c-Jun and JunD expression in rare CD11c positive dendritic cells. Our findings suggest a notable implication of JunD in the physiology of thymocytes and p-c-Jun and p-STAT3 in the physiology of TEC. The diversity of the immunotopographical distribution and the expression levels of p-c-Jun, JunB, JunD, p-STAT3, p-STAT5, and p-STAT6 indicates that they are differentially involved in the differentiation of TEC, thymocytes, and dendritic cells.

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