Thymic Crosstalk: An Overview of the Complex Cellular Interactions That Control the Establishment of T-Cell Tolerance

Irla, Magali

doi:10.1007/978-3-030-12040-5_6

Cited by 12 publications

(12 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These cells in population are exposed to a myriad of peripheral tissue antigen (PTA) peptides that are expressed and presented via MHC-II by medullary thymic epithelial cells (mTECs) to thymocytes (3-5, 10, 11). The greater the diversity of autoantigens presented by mTECs, the more comprehensive and at the same time accurate will be the self-tolerance of the T-cell population able to migrate from thymus to the periphery (3,53,54). This process must be finely controlled, if not, loss of tolerance may occur with consequences in the emergence of autoimmune reactions.…”

Section: Discussionmentioning

confidence: 99%

Aire Gene Influences the Length of the 3′ UTR of mRNAs in Medullary Thymic Epithelial Cells

et al. 2020

View full text Add to dashboard Cite

Aire is a transcriptional controller in medullary thymic epithelial cells (mTECs) modulating a set of peripheral tissue antigens (PTAs) and non-PTA mRNAs as well as miRNAs. Even miRNAs exerting posttranscriptional control of mRNAs in mTECs, the composition of miRNA-mRNA networks may differ. Under reduction in Aire expression, networks exhibited greater miRNA diversity controlling mRNAs. Variations in the number of 3'UTR binding sites of Aire-dependent mRNAs may represent a crucial factor that influence the miRNA interaction. To test this hypothesis, we analyzed through bioinformatics the length of 3'UTRs of a large set of Aire-dependent mRNAs. The data were obtained from existing RNA-seq of mTECs of wild type or Aire-knockout (KO) mice. We used computational algorithms as FASTQC, STAR and HTSEQ for sequence alignment and counting reads, DESEQ2 for the differential expression, 3USS for the alternative 3'UTRs and TAPAS for the alternative polyadenylation sites. We identified 152 differentially expressed mRNAs between these samples comprising those that encode PTAs as well as transcription regulators. In Aire KO mTECs, most of these mRNAs featured an increase in the length of their 3'UTRs originating additional miRNA binding sites and new miRNA controllers. Results from the in silico analysis were statistically significant and the predicted miRNA-mRNA interactions were thermodynamically stable. Even with no in vivo or in vitro experiments, they were adequate to show that lack of Aire in mTECs might favor the downregulation of PTA mRNAs and transcription regulators via miRNA control. This could unbalance the overall transcriptional activity in mTECs and thus the self-representation.

show abstract

Section: Discussionmentioning

confidence: 99%

Aire Gene Influences the Length of the 3′ UTR of mRNAs in Medullary Thymic Epithelial Cells

et al. 2020

View full text Add to dashboard Cite

show abstract

“…TECs subsets also provide distinct microenvironmental niches and signals essential for proper thymocyte differentiation (reviewed in [ 11 , 13 , 16 , 17 ]). Cortical TECs are required for commitment, expansion, and positive selection of thymocytes to recognize self-MHC [ 18 ], whereas medullary TECs support negative selection, which eliminates potentially autoreactive T-cells, thus, inducing self-tolerance [ 19 ] ( Figure 1 ) (reviewed in [ 20 , 21 , 22 ]).…”

Section: Thymus Compositionmentioning

confidence: 99%

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

Figueiredo

Zilhão

Neves

2020

IJMS

View full text Add to dashboard Cite

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.

show abstract

“…At present, no other cell type is known that expresses such a large set of genes [11-13]. The positive and negative selection processes are crucial for the induction of central immune tolerance that prevents aggressive autoimmunity [9, 14].…”

Section: Introductionmentioning

confidence: 99%

The absence of the autoimmune regulator gene (AIRE) impairs the three-dimensional structure of medullary thymic epithelial cell spheroids

Monteleone-Cassiano

Dernowsek

Mascarenhas

et al. 2021

Preprint

View full text Add to dashboard Cite

Besides controlling the expression of peripheral tissue antigens, the autoimmune regulator (AIRE) gene also regulates the expression of adhesion genes in medullary thymic epithelial cells (mTECs), an essential process for mTEC-thymocyte interaction for triggering the negative selection in the thymus. For these processes to occur, it is necessary that the medulla compartment forms an adequate three-dimensional (3D) architecture, preserving the thymic medulla. Previous studies have shown that AIRE knockout (KO) mice have a small and disorganized thymic medulla; however, whether Aire influences the mTEC-mTEC interaction in the maintenance of the 3D structure has been little explored. Considering that AIRE controls cell adhesion genes, we hypothesized that this gene affects 3D mTEC-mTEC interaction. To test this, we constructed an in vitro model system for mTEC spheroid formation, in which cells adhere to each other, establishing a 3D structure. The effect of Aire on mTEC-mTEC adhesion was evaluated by comparing AIRE wild type (AIREWT) versus Aire KO (AIRE-/-) mTECs. Considering the 3D spheroid model evaluated, we reported that the absence of AIRE disorganizes the 3D structure of mTEC spheroids, promotes a differential regulation of mTEC classical surface markers, and modulates genes encoding adhesion and other molecules.

show abstract

Thymic Crosstalk: An Overview of the Complex Cellular Interactions That Control the Establishment of T-Cell Tolerance

Cited by 12 publications

References 96 publications

Aire Gene Influences the Length of the 3′ UTR of mRNAs in Medullary Thymic Epithelial Cells

Aire Gene Influences the Length of the 3′ UTR of mRNAs in Medullary Thymic Epithelial Cells

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

The absence of the autoimmune regulator gene (AIRE) impairs the three-dimensional structure of medullary thymic epithelial cell spheroids

Contact Info

Product

Resources

About