Nejvíce citovaný článek - PubMed ID 17322887
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
Antigen-presenting cells (APCs) are master regulators of the immune response by directly interacting with T cells to orchestrate distinct functional outcomes. Several types of professional APC exist, including conventional dendritic cells, B cells and macrophages, and numerous other cell types have non-classical roles in antigen presentation, such as thymic epithelial cells, endothelial cells and granulocytes. Accumulating evidence indicates the presence of a new family of APCs marked by the lineage-specifying transcription factor retinoic acid receptor-related orphan receptor-γt (RORγt) and demonstrates that these APCs have key roles in shaping immunity, inflammation and tolerance, particularly in the context of host-microorganism interactions. These RORγt+ APCs include subsets of group 3 innate lymphoid cells, extrathymic autoimmune regulator-expressing cells and, potentially, other emerging populations. Here, we summarize the major findings that led to the discovery of these RORγt+ APCs and their associated functions. We discuss discordance in recent reports and identify gaps in our knowledge in this burgeoning field, which has tremendous potential to advance our understanding of fundamental immune concepts.
- MeSH
- antigen prezentující buňky metabolismus MeSH
- endoteliální buňky MeSH
- jaderné receptory - podrodina 1, skupina F, člen 3 * metabolismus MeSH
- lidé MeSH
- lymfocyty * MeSH
- přirozená imunita MeSH
- transportní proteiny metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- jaderné receptory - podrodina 1, skupina F, člen 3 * MeSH
- transportní proteiny MeSH
Ameloblasts are specialized epithelial cells in the jaw that have an indispensable role in tooth enamel formation-amelogenesis1. Amelogenesis depends on multiple ameloblast-derived proteins that function as a scaffold for hydroxyapatite crystals. The loss of function of ameloblast-derived proteins results in a group of rare congenital disorders called amelogenesis imperfecta2. Defects in enamel formation are also found in patients with autoimmune polyglandular syndrome type-1 (APS-1), caused by AIRE deficiency3,4, and in patients diagnosed with coeliac disease5-7. However, the underlying mechanisms remain unclear. Here we show that the vast majority of patients with APS-1 and coeliac disease develop autoantibodies (mostly of the IgA isotype) against ameloblast-specific proteins, the expression of which is induced by AIRE in the thymus. This in turn results in a breakdown of central tolerance, and subsequent generation of corresponding autoantibodies that interfere with enamel formation. However, in coeliac disease, the generation of such autoantibodies seems to be driven by a breakdown of peripheral tolerance to intestinal antigens that are also expressed in enamel tissue. Both conditions are examples of a previously unidentified type of IgA-dependent autoimmune disorder that we collectively name autoimmune amelogenesis imperfecta.
- MeSH
- ameloblasty metabolismus MeSH
- amelogenesis imperfecta * komplikace imunologie MeSH
- antigeny imunologie metabolismus MeSH
- autoimunitní polyglandulární syndromy * komplikace imunologie MeSH
- autoprotilátky * imunologie MeSH
- celiakie * komplikace imunologie MeSH
- imunoglobulin A imunologie MeSH
- lidé MeSH
- protein AIRE nedostatek MeSH
- proteiny imunologie metabolismus MeSH
- střeva imunologie metabolismus MeSH
- zubní sklovina imunologie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- AIRE protein, human MeSH Prohlížeč
- antigeny MeSH
- autoprotilátky * MeSH
- imunoglobulin A MeSH
- protein AIRE MeSH
- proteiny 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 inevitability of evolution of the adaptive immune system with its mechanism of randomly rearranging segments of the T cell receptor (TCR) gene is the generation of self-reactive clones. For the sake of prevention of autoimmunity, these clones must be eliminated from the pool of circulating T cells. This process occurs largely in the thymic medulla where the strength of affinity between TCR and self-peptide MHC complexes is the factor determining thymocyte fate. Thus, the display of self-antigens in the thymus by thymic antigen presenting cells, which are comprised of medullary thymic epithelial (mTECs) and dendritic cells (DCs), is fundamental for the establishment of T cell central tolerance. Whereas mTECs produce and present antigens in a direct, self-autonomous manner, thymic DCs can acquire these mTEC-derived antigens by cooperative antigen transfer (CAT), and thus present them indirectly. While the basic characteristics for both direct and indirect presentation of self-antigens are currently known, recent reports that describe the heterogeneity of mTEC and DC subsets, their presentation capacity, and the potentially non-redundant roles in T cell selection processes represents another level of complexity which we are attempting to unravel. In this review, we underscore the seminal studies relevant to these topics with an emphasis on new observations pertinent to the mechanism of CAT and its cellular trajectories underpinning the preferential distribution of thymic epithelial cell-derived self-antigens to specific subsets of DC. Identification of molecular determinants which control CAT would significantly advance our understanding of how the cellularly targeted presentation of thymic self-antigens is functionally coupled to the T cell selection process.
- Klíčová slova
- antigen presentation, central tolerance, cooperative antigen transfer, dendritic cells, thymic epithelial cells, thymus,
- MeSH
- autoantigeny * MeSH
- centrální tolerance MeSH
- dendritické buňky * MeSH
- epitelové buňky MeSH
- receptory antigenů T-buněk MeSH
- thymus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- autoantigeny * MeSH
- receptory antigenů T-buněk MeSH
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
- antigeny CD14 metabolismus MeSH
- autoantigeny imunologie MeSH
- autotolerance MeSH
- chemokiny imunologie metabolismus MeSH
- dendritické buňky imunologie MeSH
- epitelové buňky imunologie metabolismus MeSH
- kolitida imunologie 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
- antigeny CD14 MeSH
- autoantigeny MeSH
- Cd14 protein, mouse MeSH Prohlížeč
- chemokiny MeSH
- receptory imunologické MeSH
- Sirpa protein, mouse MeSH Prohlížeč
- toll-like receptory MeSH
The autoimmune regulator (Aire) serves an essential function for T cell tolerance by promoting the "promiscuous" expression of tissue antigens in thymic epithelial cells. Aire is also detected in rare cells in peripheral lymphoid organs, but the identity of these cells is poorly understood. Here, we report that Aire protein-expressing cells in lymph nodes exhibit typical group 3 innate lymphoid cell (ILC3) characteristics such as lymphoid morphology, absence of "classical" hematopoietic lineage markers, and dependence on RORγt. Aire+ cells are more frequent among lineage-negative RORγt+ cells of peripheral lymph nodes as compared with mucosa-draining lymph nodes, display a unique Aire-dependent transcriptional signature, express high surface levels of MHCII and costimulatory molecules, and efficiently present an endogenously expressed model antigen to CD4+ T cells. These findings define a novel type of ILC3-like cells with potent APC features, suggesting that these cells serve a function in the control of T cell responses.
- MeSH
- adhezní molekula epiteliálních buněk metabolismus MeSH
- antigen prezentující buňky imunologie MeSH
- antigeny CD11 metabolismus MeSH
- fenotyp MeSH
- genetická transkripce MeSH
- histokompatibilita - antigeny třídy II metabolismus MeSH
- jaderné receptory - podrodina 1, skupina F, člen 3 metabolismus MeSH
- lymfatické uzliny cytologie MeSH
- lymfocyty imunologie metabolismus MeSH
- myši inbrední BALB C MeSH
- myši knockoutované MeSH
- myši MeSH
- přirozená imunita MeSH
- protein AIRE MeSH
- regulace genové exprese MeSH
- transkripční faktory genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adhezní molekula epiteliálních buněk MeSH
- antigeny CD11 MeSH
- histokompatibilita - antigeny třídy II MeSH
- Itgax protein, mouse MeSH Prohlížeč
- jaderné receptory - podrodina 1, skupina F, člen 3 MeSH
- Rorc protein, mouse MeSH Prohlížeč
- transkripční faktory MeSH
