The Cellular Mechanism of Aire Control of T Cell Tolerance

Anderson, Mark S.; Venanzi, Emily S.; Chen, Zhibin; Berzins, Stuart P.; Benoist, Christophe; Mathis, Diane

doi:10.1016/j.immuni.2005.07.005

Cited by 575 publications

(630 citation statements)

References 43 publications

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“…1C). These results are broadly consistent with previous studies that looked more specifically at Treg using anti-FOXP3 staining (required for definitive Treg identification) in conjunction with markers such as CD4 and CD25 and which reported no significant change in Treg numbers in Aire-deficient mice [8,10].…”

Section: Nkt Cell Frequencysupporting

confidence: 91%

“…An alternate explanation is that the loss of Aire might affect more than one form of tolerance [2,8,9]. A controversial, but still unresolved, possibility is that Aire-dependent antigens could be important for the development of regulatory T cells in the thymus, perhaps leading Aire-deficient mice to develop regulatory T cell deficiencies already known to be associated with autoimmunity [4,5,[10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

“…In the case of Treg, multiple studies have now demonstrated that their absolute number, frequency and function are unaffected in the absence of Aire [1,2,8,10]. There is some evidence of an impact on the antigen specificity of the Treg repertoire, but no obvious defect likely to contribute to autoimmunity in Aire-deficient individuals [10,13].…”

Section: Introductionmentioning

confidence: 99%

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NKT cell development in the absence of the autoimmune regulator gene (Aire)

et al. 2008

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Autoimmune regulator gene (Aire)-deficient mice develop an array of autoimmune lesions that reflect failures of immune tolerance. Negative selection is clearly compromised in these mice, but there is evidence to suggest that other mechanisms of tolerance might also be affected, including a possible impairment of regulatory T cell (Treg) development. Studies to date have failed to demonstrate any significant impact on the development or function of the FOXP3 1 Treg compartment, but NKT cells represent a distinct regulatory cell lineage that also develop in the thymus and which are known to influence selftolerance. Aire-related defects coincide with NKT cell deficiencies in a number of animal models, but the direct consequence of Aire-deficiency on NKT cell development has not been established. In this study, we demonstrate that the frequency, distribution and cytokine production of NKT cells and their subsets is principally normal in Aire-deficient mice. We conclude that Aire has little or no effect on regulatory T cell development in general and NKT cells in particular.

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Section: Nkt Cell Frequencysupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NKT cell development in the absence of the autoimmune regulator gene (Aire)

et al. 2008

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“…Interestingly, in a recent report the thymic expression of mRNA encoding the self antigens insulin and cytochrome P4501A2 [51] in two patients with Omenn syndrome and one SCID patient was absent, and, in addition, mTEC from the patients lacked Aire expression [52], suggesting that the few T cells carrying a restricted TCR repertoire may escape negative selection and cause autoimmunity in the periphery. Conversely, Aire -/-mice were recently reported to target the salivary gland autoantigen afodrin in spite of normal a-fodrin mRNA levels in mTEC [28], suggesting additional factors or mechanisms determining the organ-specific autoimmunity caused by Aire deficiency, an idea which has recently been reviewed by Mathis et al [53]. Evidence is accumulating that Aire regulates ectopic expression of only a subset of self antigens in mature mTEC [27].…”

Section: Discussionmentioning

confidence: 99%

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

et al. 2006

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Patients with autoimmune polyendocrine syndrome type I (APS I)suffer from endocrine and non-endocrine disorders due to mutations in the autoimmune regulator gene (AIRE). Mouse Aire is expressed both in thymic medullary epithelial cells and in peripheral antigen-presenting cells, suggesting a role in both central and peripheral tolerance. We here report that Aire -/-dendritic cells (DC) activate naive T cells more efficiently than do Aire +/+ DC. Expression array analyses of Aire -/-DC revealed differential regulation of 68 transcripts, among which, the vascular cell adhesion molecule-1 (VCAM-1) transcript was up-regulated in Aire -/-DC. Concurrently, the expression of the VCAM-1 protein was up-regulated on both Aire -/-DC and monocytes from APS I patients. Blocking the interaction of VCAM-1 prevented enhanced Aire -/-DC stimulation of T cell hybridomas. We determined an increased number of DC in spleen and lymph nodes and of monocytes in the blood from Aire -/-mice, and an increased number of blood monocytes in APS I patients. Our findings imply a role for Aire in peripheral DC regulation of T cell activation, and suggest that Aire participates in peripheral tolerance.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35240_s.pdf IntroductionInactivation of the autoimmune regulator gene (AIRE) [1][2][3] causes autoimmunity in patients with autoimmune polyendocrine syndrome type I (APS I, APECED, OMIM 240300) and in a gene targeted mouse model [4,5]. APS I is a rare monogenic autosomal recessive disease without HLA association [6,7], which is prevalent in isolated populations [8][9][10]. APS I patients develop a progressive loss of tolerance against self antigens and suffer from multiorgan failures due to the immunological destruction of adrenals, parathyroid glands and b cells of the islets of Langerhans [11]. Many of the APS I organ-specific autoantigens have been identified and characterized [12,13]. In addition, as a sign of immune dysfunction, these patients have difficulties clearing Candida albicans infections in mucosal membranes [14]. Functional studies of AIRE suggest a role as a transcription factor and in vitro transactivating studies support this notion [15][16][17][18]. Moreover, the PHD1 domain of AIRE has been suggested to have an E3 ubiquitin ligase activity in cell-free assays [19], findings in variance with a recent report [20]. Aire is highly expressed in a subset of the medullary thymic epithelial cells (mTEC) as well as in DC in the spleen and lymph nodes [21][22][23][24], indicating a potential role in immunological tolerance.To characterize the function of Aire, we previously engineered an Aire-deficient mouse targeting the most common APS I mutation [4]. Aire-deficient mice develop multiple organ-specific autoantibodies and lymphocytic infiltrates, thus mimicking some of the features of human APS I [4]. Subsequently, the role of Aire in negative selection was demonstrated [5]. These findings were further supported using TCR transgenic mic...

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“…Third, the average residence time of mature thymocytes of 4 to 5 days is shorter than previously assumed [31,32]. Nevertheless, deletion of monoclonal or polyclonal T-cell repertoires specific for ectopically expressed (neo) self-antigens is highly efficient [33,34]. Since Spatial is also expressed at a limiting dose in mature mTEC, these features qualify it as preferential target of an auto-immune response.…”

Section: Spatial Is Expressed In Mature Medullary Thymic Epithelial Cmentioning

confidence: 95%

Spatial (Tbata) expression in mature medullary thymic epithelial cells

et al. 2010

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The Spatial gene is expressed in highly polarized cell types such as testis germ cells, brain neurons and thymic epithelial cells (TEC). Its expression was documented in testis and brain but poorly characterized in thymus. Here, we characterize for the first time Spatial-expressing TEC throughout ontogeny and adult mouse thymus. Spatial is expressed in thymicfated domain by embryonic day E10.5 and persists in subcapsular, cortical, medullary epithelial cells and in MTS24 1 progenitor TEC. Using mouse strains in which thymocyte development is blocked at various stages, we show that Spatial expression is independent of thymocyte-derived signals during thymus organogenesis. Analyses on purified thymic cell subsets show that Spatial short isoforms are expressed in cortical TEC (cTEC) and mature medullary TEC (mTEC). Spatial long isoforms were detected in the same TEC population. Spatial presents a nuclear distribution specific to mature mTEC expressing UEA1 and Aire. Aire-and RANKL-deficient mice revealed that Spatial expression is drastically reduced in the thymus of these mutants. These findings reveal a critical function of Aire in regulating Spatial expression, which is compatible with promiscuous Spatial gene expression. 530 IntroductionThe vertebrate thymus is responsible for the production of functional nonautoreactive T lymphocytes. In this primary lymphoid organ, T-cell precursors commonly called thymocytes undergo a series of developmental stages through interactions with thymic stromal cells, resulting in the generation of mature T lymphocytes that are exported to the periphery [1,2]. The unique function of the thymus resides mainly in the thymic epithelium, which forms the major subcompartment of the stroma [3,4]. The thymic epithelium itself is commonly divided into two main regions, the cortex and the medulla, and each of these regions contains several ultrastructurally and phenotypically distinct types of thymic epithelial cells (TEC) [5,6]. TEC are required both for thymus organogenesis and for the promotion of most if not all stages of thymocyte maturation [3,4]. Understanding the molecular mechanisms regulating TEC differentiation and function provides crucial insights into mechanisms controlling T-cell development in the thymus.Using DNA chip technology we isolated the Spatial gene (Stromal Protein Associated with Thymii and Lymph node), also known as Tbata (thymus, brain and testes associated), by an approach based on differential screening between different knock-out mice models exhibiting distinct thymic immunodeficiencies [7]. This analysis led to the identification of three adult variants of the Spatial gene expressed in the thymus [8]. In addition, we also described two other isoforms isolated in the testis [8][9][10]. According to the size of alternative spliced variants, we have respectively named Spatial isoforms: Spatial-a (1035 bp), Spatial-b (1002 bp), Spatial-g (933 bp) for the short isoforms identified in the thymus; Spatial-d (1353 bp) and Spatial-e (1454 bp) for the long isoforms ...

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The Cellular Mechanism of Aire Control of T Cell Tolerance

Cited by 575 publications

References 43 publications

NKT cell development in the absence of the autoimmune regulator gene (Aire)

NKT cell development in the absence of the autoimmune regulator gene (Aire)

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

Spatial (Tbata) expression in mature medullary thymic epithelial cells

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