Modulation of Aire regulates the expression of tissue-restricted antigens

Kont, Vivian; Laan, Martti; Kisand, Kai; Merits, Andres; Scott, Hamish S.; Peterson, Pärt

doi:10.1016/j.molimm.2007.05.014

Cited by 90 publications

(83 citation statements)

References 46 publications

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“…Previous work by Peterson et al (27) showed that overexpression of murine Aire in vitro results in an increased expression of TRAs. To examine whether the increased expression of AIRE in DS thymus leads to an altered expression of TRAs, the expression of both AIRE-dependent and AIRE-independent TRAs was analyzed.…”

Section: Discussionmentioning

confidence: 97%

Altered Expression of Autoimmune Regulator in Infant Down Syndrome Thymus, a Possible Contributor to an Autoimmune Phenotype

Skogberg

Lundberg

Lindgrén

et al. 2014

The Journal of Immunology

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Down syndrome (DS), caused by trisomy of chromosome 21, is associated with immunological dysfunctions such as increased frequency of infections and autoimmune diseases. Patients with DS share clinical features, such as autoimmune manifestations and specific autoantibodies, with patients affected by autoimmune polyendocrine syndrome type 1. Autoimmune polyendocrine syndrome type 1 is caused by mutations in the autoimmune regulator (AIRE) gene, located on chromosome 21, which regulates the expression of tissue-restricted Ags (TRAs) in thymic epithelial cells. We investigated the expression of AIRE and TRAs in DS and control thymic tissue using quantitative PCR. AIRE mRNA levels were elevated in thymic tissue from DS patients, and trends toward increased expression of the AIRE-controlled genes INSULIN and CHRNA1 were found. Immunohistochemical stainings showed altered cell composition and architecture of the thymic medulla in DS individuals with increased frequencies of AIRE-positive medullary epithelial cells and CD11c-positive dendritic cells as well as enlarged Hassall’s corpuscles. In addition, we evaluated the proteomic profile of thymic exosomes in DS individuals and controls. DS exosomes carried a broader protein pool and also a larger pool of unique TRAs compared with control exosomes. In conclusion, the increased AIRE gene dose in DS could contribute to an autoimmune phenotype through multiple AIRE-mediated effects on homeostasis and function of thymic epithelial cells that affect thymic selection processes.

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Section: Discussionmentioning

confidence: 97%

Altered Expression of Autoimmune Regulator in Infant Down Syndrome Thymus, a Possible Contributor to an Autoimmune Phenotype

Skogberg

Lundberg

Lindgrén

et al. 2014

The Journal of Immunology

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“…Aire is primarily known for its ability to promote TSA expression [5,16,37]. Indeed, transcript analysis of mTEC hi cells from CNS1-KO mice showed a striking downregulation of Aire-dependent genes Tff3, Spt1, Ins2, and Saa1, whereas Aire-independent genes Csnb and Gad1 were largely unaffected ( Fig.…”

Section: Cns1-knockout Thymus Has An Aire-deficient Phenotypementioning

confidence: 94%

A highly conserved NF‐κB‐responsive enhancer is critical for thymic expression of Aire in mice

et al. 2015

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Autoimmune regulator (Aire) has a unique expression pattern in thymic medullary epithelial cells (mTECs), in which it plays a critical role in the activation of tissue-specific antigens. The expression of Aire in mTECs is activated by receptor activator of nuclear factor κB (RANK) signaling; however, the molecular mechanism behind this activation is unknown. Here, we characterize a conserved noncoding sequence 1 (CNS1) containing two NF-κB binding sites upstream of the Aire coding region. We show that CNS1-deficient mice lack thymic expression of Aire and share several features of Aire-knockout mice, including downregulation of Aire-dependent genes, impaired terminal differentiation of the mTEC population, and reduced production of thymic Treg cells. In addition, we show that CNS1 is indispensable for RANK-induced Aire expression and that CNS1 is activated by NF-κB pathway complexes containing RelA. Together, our results indicate that CNS1 is a critical link between RANK signaling, NF-κB activation, and thymic expression of Aire.Keywords: Autoimmune regulator · Enhancer · NF-κB · Receptor activator of nuclear factor κB · Thymic medulla See accompanying Commentary by Mitsuru MatsumotoAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionCentral tolerance is achieved in the thymus by selection of a T-cell repertoire that is nonreactive to self. In the thymus, developing T cells, termed thymocytes, interact with cortical thymic epithelial cells and thymic medullary epithelial cells (cTECs and mTECs) and dendritic cells that present antigens during the positive and negative selection processes [1,2]. Due to their unique ability to express a wide range of peripheral tissue-specific antigens (TSAs), mTECs are believed to play a central role in the negative selection of self-reactive thymocytes and thereby securing tolerance to self-proteins [3,4]. The promiscuous expression of peripheral antigens in mTECs is largely controlled by autoimmune regulator Correspondence: Dr. Pärt Peterson e-mail: part.peterson@ut.ee (Aire) that constitutively promotes the transcription of hundreds of tissue-specific genes [5][6][7][8]. The importance of Aire in negative selection is exemplified by the mutations in the human Aire gene, which cause a monogenic disorder called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy [9][10][11]. Similar to human autoimmune polyendocrinopathy-candidiasisectodermal dystrophy patients, Aire-deficient mice exhibit a multiorgan autoimmune phenotype [5], although some clear differences exist including a lack of endocrine organ involvement, relatively mild disease, and the lack of high-titer neutralizing auto-Abs to type 1 interferons and interleukin 22 [12,13].The Aire protein has a unique and highly specific expression profile. Aire is rapidly upregulated for a few days [14,15] [17,24,[26][27][28]. RANK ligation activates both the classical and alternative pathways of NF-κB signaling [29]. The classical pathway involves t...

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“…Although pGE is preserved in fetal thymic organ cultures (FTOCs) and reaggregate thymic organ cultures, it is invariably lost in two-dimensional (2D) cultures of isolated TECs. Likewise, expression of Aire, a main molecular driver of pGE, and expression of FoxN1, the transcription factor specifying the function of TECs, are rapidly downregulated in 2D TEC cultures (14,(18)(19)(20). Lack of a reductionist in vitro culture system of mTECs has hampered the analysis of the molecular regulation of pGE, given the limited amount of mTECs that can be isolated ex vivo and the lack of suitable TEC lines.…”

mentioning

confidence: 99%

An Organotypic Coculture Model Supporting Proliferation and Differentiation of Medullary Thymic Epithelial Cells and Promiscuous Gene Expression

Pinto

Schmidt

Egle

et al. 2013

The Journal of Immunology

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Understanding intrathymic T cell differentiation has been greatly aided by the development of various reductionist in vitro models that mimic certain steps/microenvironments of this complex process. Most models focused on the faithful in vitro restoration of T cell differentiation and selection. In contrast, suitable in vitro models emulating the developmental pathways of the two major thymic epithelial cell lineages—cortical thymic epithelial cells and medullary thymic epithelial cells (mTECs)—are yet to be developed. In this regard, lack of an in vitro model mimicking the developmental biology of the mTEC lineage has hampered the molecular analysis of the so-called “promiscuous expression” of tissue-restricted genes, a key property of terminally differentiated mTECs. Based on the close biological relationship between the skin and thymus epithelial cell compartments, we adapted a three-dimensional organotypic coculture model, originally developed to provide a bona fide in vitro dermal equivalent, for the culture of isolated mTECs. This three-dimensional model preserves key features of mTECs: proliferation and terminal differentiation of CD80lo, Aire− mTECs into CD80hi, Aire+ mTECs; responsiveness to RANKL; and sustained expression of FoxN1, Aire, and tissue-restricted genes in CD80hi mTECs. This in vitro culture model should facilitate the identification of molecular components and pathways involved in mTEC differentiation in general and in promiscuous gene expression in particular.

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Modulation of Aire regulates the expression of tissue-restricted antigens

Cited by 90 publications

References 46 publications

Altered Expression of Autoimmune Regulator in Infant Down Syndrome Thymus, a Possible Contributor to an Autoimmune Phenotype

Altered Expression of Autoimmune Regulator in Infant Down Syndrome Thymus, a Possible Contributor to an Autoimmune Phenotype

A highly conserved NF‐κB‐responsive enhancer is critical for thymic expression of Aire in mice

An Organotypic Coculture Model Supporting Proliferation and Differentiation of Medullary Thymic Epithelial Cells and Promiscuous Gene Expression

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