Nejvíce citovaný článek - PubMed ID 29193031
A novel conditional Aire allele enables cell-specific ablation of the immune tolerance regulator Aire
Since its discovery, Aire has been the topic of numerous studies in its role as a transcriptional regulator in the thymus where it promotes the "promiscuous" expression of a large repertoire of tissue-restricted antigens (TRAs) that are normally expressed only in the immune periphery. This process occurs in specialized medullary thymic epithelial cells (mTECs) and mediates the elimination of self-reactive T cells or promotes their conversion to the Foxp3+ regulatory T cell lineage, both of which are required for the prevention of autoimmunity. In recent years, there has been increasing interest in the role of extrathymic Aire expression in peripheral organs. The focus has primarily been on the identification of the cellular source(s) and mechanism(s) by which extrathymic AIRE affects tolerance-related or other physiological processes. A cadre of OMICs tools including single cell RNA sequencing and novel transgenic models to trace Aire expression to perform lineage tracing experiments have shed light on a phenomenon that is more complex than previously thought. In this chapter, we provide a deeper analysis of how extrathymic Aire research has developed and progressed, how cellular sources were identified, and how the function of AIRE was determined. Current data suggests that extrathymic AIRE fulfills a function that differs from what has been observed in the thymus and strongly argues that its main purpose is to regulate transcriptional programs in a cell content-dependent manner. Surprisingly, there is data that also suggests a non-transcriptional role of extrathymic AIRE in the cytoplasm. We have arrived at a potential turning point that will take the field from the classical understanding of AIRE as a transcription factor in control of TRA expression to its role in immunological and non-immunological processes in the periphery.
- Klíčová slova
- AIRE, Fertility, Immune periphery, Non-immune function, RORγt+ eTACs, Sertoli cells, Th17 responses, Transcription function, eTACs, mTECs,
- MeSH
- antigeny MeSH
- autoimunita MeSH
- epitelové buňky metabolismus MeSH
- regulace genové exprese * MeSH
- thymus MeSH
- transkripční faktory * genetika metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antigeny MeSH
- transkripční faktory * MeSH
Male infertility affects approximately 14% of all European men, of which ~44% are characterized as idiopathic. There is an urgency to identify the factors that affect male fertility. One such factor, Autoimmune Regulator (AIRE), a protein found in the thymus, has been studied in the context of central tolerance functioning as a nuclear transcription modulator, responsible for the expression of tissue-restricted antigens in specialized thymic cells that prevent autoimmunity. While its expression in the testes remains enigmatic, we recently observed that sterility in mice correlates with the absence of Aire in the testes, regardless of the deficient expression in medullary thymic epithelial cells or cells of the hematopoietic system. By assessing the Aire transcript levels, we discovered that Sertoli cells are the exclusive source of Aire in the testes, where it most likely plays a non-immune role, suggesting an unknown mechanism by which testicular Aire regulates fertility. Here, we discuss these results in the context of previous reports which have suggested that infertility observed in Aire deficient mice is of an autoimmune aetiology. We present an alternative point of view for the role of Aire in testes in respect to fertility altering the perspective of how Aire's function in the testes is currently perceived.
- Klíčová slova
- Aire 1, Sertoli cells 5, autoimmunity 2, spermatogenesis 6, sterility 3, testis 4,
- MeSH
- autoimunita * MeSH
- buněčné jádro MeSH
- epitelové buňky * metabolismus MeSH
- fertilita MeSH
- myši MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Patients with loss of function in the gene encoding the master regulator of central tolerance AIRE suffer from a devastating disorder called autoimmune polyendocrine syndrome type 1 (APS-1), characterized by a spectrum of autoimmune diseases and severe mucocutaneous candidiasis. Although the key mechanisms underlying the development of autoimmunity in patients with APS-1 are well established, the underlying cause of the increased susceptibility to Candida albicans infection remains less understood. Here, we show that Aire+MHCII+ type 3 innate lymphoid cells (ILC3s) could sense, internalize and present C. albicans and had a critical role in the induction of Candida-specific T helper 17 (TH17) cell clones. Extrathymic Rorc-Cre-mediated deletion of Aire resulted in impaired generation of Candida-specific TH17 cells and subsequent overgrowth of C. albicans in the mucosal tissues. Collectively, our observations identify a previously unrecognized regulatory mechanism for effective defense responses against fungal infections.
The development of thymic regulatory T cells (Treg) is mediated by Aire-regulated self-antigen presentation on medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), but the cooperation between these cells is still poorly understood. Here we show that signaling through Toll-like receptors (TLR) expressed on mTECs regulates the production of specific chemokines and other genes associated with post-Aire mTEC development. Using single-cell RNA-sequencing, we identify a new thymic CD14+Sirpα+ population of monocyte-derived dendritic cells (CD14+moDC) that are enriched in the thymic medulla and effectively acquire mTEC-derived antigens in response to the above chemokines. Consistently, the cellularity of CD14+moDC is diminished in mice with MyD88-deficient TECs, in which the frequency and functionality of thymic CD25+Foxp3+ Tregs are decreased, leading to aggravated mouse experimental colitis. Thus, our findings describe a TLR-dependent function of mTECs for the recruitment of CD14+moDC, the generation of Tregs, and thereby the establishment of central tolerance.
- MeSH
- analýza jednotlivých buněk MeSH
- autoantigeny imunologie MeSH
- autotolerance MeSH
- chemokiny imunologie metabolismus MeSH
- dendritické buňky imunologie MeSH
- epitelové buňky imunologie metabolismus MeSH
- kolitida imunologie MeSH
- lipopolysacharidové receptory metabolismus MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- převzatá imunita MeSH
- prezentace antigenu MeSH
- průtoková cytometrie MeSH
- receptory imunologické metabolismus MeSH
- regulační T-lymfocyty imunologie transplantace MeSH
- sekvenční analýza RNA MeSH
- separace buněk MeSH
- signální transdukce imunologie MeSH
- thymus cytologie imunologie MeSH
- toll-like receptory metabolismus MeSH
- upregulace MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- autoantigeny MeSH
- Cd14 protein, mouse MeSH Prohlížeč
- chemokiny MeSH
- lipopolysacharidové receptory MeSH
- receptory imunologické MeSH
- Sirpa protein, mouse MeSH Prohlížeč
- toll-like receptory MeSH
