Promiscuous gene expression and central T-cell tolerance: More than meets the eye

Tumor Immunology Program, Division of Cellular Immunology, German Cancer Research Center, INF 280, D-69120 Heidelberg, Germany.
Trends in Immunology (Impact Factor: 10.4). 08/2002; 23(7):364-71. DOI: 10.1016/S1471-4906(02)02248-2
Source: PubMed


Self-tolerance of the T-cell repertoire is mediated by multiple mechanisms operating both in the thymus ('central tolerance') and in peripheral lymphoid and non-lymphoid organs ('peripheral tolerance'). Based on the recent finding that tissue-specific genes are commonly expressed in the thymus, this strict delineation has been blurred. Medullary thymic epithelial cells have been identified as a unique cell type that expresses a wide range of tissue-specific genes in a 'promiscuous' manner and displays these self-antigens for intrathymic repertoire selection. The array of promiscuously expressed genes appears random rather than the result of specific selection. The gains and pitfalls of this tolerance mechanism have important implications for autoimmunity.

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    • "The discovery that PTAs are ectopically expressed in the thymic medulla by mTECs that contribute to the elimination of nascent autoreactive thymocytes throughout negative selection has improved our understanding of the molecular and genetic mechanisms controlling central tolerance (Kyewski et al. 2002). mTECs express virtually all PTAs, and this guarantees the representation of autoantigens from all tissues and organs. "
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    ABSTRACT: The downregulation of PTA genes in mTECs is associated with the loss of self-tolerance, and the role of miRNAs in this process is not fully understood. Therefore, we studied the expression of mRNAs and miRNAs in mTECs from autoimmune NOD mice during the period when loss of self-tolerance occurs in parallel with non-autoimmune BALB/c mice. Although the expression of the transcriptional regulator Aire was unchanged, we observed downregulation of a set of PTA mRNAs. A set of miRNAs was also differentially expressed in these mice. The reconstruction of miRNA-mRNA interaction networks identified the controller miRNAs and predicted the PTA mRNA targets. Interestingly, the known Aire-dependent PTAs exhibited pronounced refractoriness in the networking interaction with miRNAs. This study reveals the existence of a new mechanism in mTECs, and this mechanism may have importance in the control of self-tolerance.
    Immunobiology 08/2014; 220(1). DOI:10.1016/j.imbio.2014.08.015 · 3.04 Impact Factor
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    • "The autoimmune regulator (Aire) gene encodes a DNA-binding protein that functions as a transcription factor (TF) controlling the ectopic expression of peripheral tissue antigens (PTAs) by medullary thymic epithelial cells (mTECs). The biological function of this gene is closely associated with the negative selection of autoreactive thymocytes, consequently preventing aggressive autoimmunity and autoimmune diseases (Kyewski et al. 2002; Gallegos and Bevan 2006; Tikocinski et al. 2008; Mathis and Benoist 2009; Tanigushi and Anderson 2011). "
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    ABSTRACT: The autoimmune regulator (Aire) is a transcription factor that controls the ectopic expression of a large set of peripheral tissue antigen (PTA) genes in medullary thymic epithelial cells (mTECs). Recent evidence has demonstrated that Aire releases stalled RNA polymerase II (RNA Pol II) from blockage at the promoter region of its target genes. Given that, in addition to messenger RNAs (mRNA), RNA Pol II also transcribes microRNAs (miRNAs), we raised the hypothesis that Aire might play a role as an upstream controller of miRNA transcription. To test this, we initially analyzed the expression profiles of 662 miRNAs in control and Aire-silenced (siRNA) murine mTEC 3.10 cells using microarrays. The bioinformatics programs SAM and Cluster-TreeView were then used to identify the differentially expressed miRNAs and their profiles, respectively. Thirty Aire-dependent miRNAs were identified in the Aire-silenced mTECs, of which 18 were up- and 12 were down-regulated. The down-regulated miR-376 family was the focus of this study because its members (miR-376a, miR-376b and miR-376c) are located in the genome within the Gm2922 open-reading frame (ORF) gene segment on the chromosome 12F1. The T-boxes (TTATTA) and G-boxes (GATTGG), which represent putative RNA Pol II promoter motifs, were located in a portion spanning 10kb upstream of the ATG codon of Gm2922. Moreover, we found that Gm2922 encodes an mRNA, which was also down-regulated in Aire-silenced mTECs. These results represent the first evidence that Aire can play a role as a controller of transcription of miRNAs located within genomic regions encompassing ORF and/or mRNA genes.
    Immunobiology 07/2012; 218(4). DOI:10.1016/j.imbio.2012.06.013 · 3.04 Impact Factor
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    • "The discovery of promiscuous gene expression (PGE) in the thymus allowed a better understanding for central tolerance in the generation of the T cell repertoire, consequently placing a mechanism for self versus non-self discrimination by T lymphocytes (Kyewski et al., 2002; Gallegos and Bevan, 2006; Tikocinski et al., 2008). Accordingly, the main implication of this heterogeneous gene expression in the thymus is associated with the maintenance of the immunological homeostasis in the body, controlling the pathogenic autoimmune reactions. "
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    ABSTRACT: The expression of peripheral tissue antigens (PTAs) in the thymus by medullary thymic epithelial cells (mTECs) is essential for the central self-tolerance in the generation of the T cell repertoire. Due to heterogeneity of autoantigen representation, this phenomenon has been termed promiscuous gene expression (PGE), in which the autoimmune regulator (Aire) gene plays a key role as a transcription factor in part of these genes. Here we used a microarray strategy to access PGE in cultured murine CD80(+) 3.10 mTEC line. Hierarchical clustering of the data allowed observation that PTA genes were differentially expressed being possible to found their respective induced or repressed mRNAs. To further investigate the control of PGE, we tested the hypothesis that genes involved in this phenomenon might also be modulated by transcriptional network. We then reconstructed such network based on the microarray expression data, featuring the guanylate cyclase 2d (Gucy2d) gene as a main node. In such condition, we established 167 positive and negative interactions with downstream PTA genes. Silencing Aire by RNA interference, Gucy2d while down regulated established a larger number (355) of interactions with PTA genes. T- and G-boxes corresponding to AIRE protein binding sites located upstream to ATG codon of Gucy2d supports this effect. These findings provide evidence that Aire plays a role in association with Gucy2d, which is connected to several PTA genes and establishes a cascade-like transcriptional control of promiscuous gene expression in mTEC cells.
    Molecular Immunology 09/2009; 46(16):3240-4. DOI:10.1016/j.molimm.2009.08.002 · 2.97 Impact Factor
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