Aire regulates negative selection of organ-specific T cells

Liston, Adrian; Lesage, Sylvie; Wilson, J. A.; Peltonen, Leena; Goodnow, Christopher C.

doi:10.1038/ni906

Cited by 703 publications

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“…An alteration of the delicate balance in both central and peripheral tolerance mechanisms may account for the development of autoimmune disorders. Recent studies have documented the importance of Aire in maintaining central tolerance in vivo [5,25,50]. Investigation of mRNA from mTEC revealed an under-representation of certain transcripts in the absence of Aire, implicating a mechanism for Aire in regulating ectopic expression of tissue-specific genes in the thymus [5].…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, the role of Aire in negative selection was demonstrated [5]. These findings were further supported using TCR transgenic mice expressing hen egg lysozyme (HEL) as a surrogate organ-specific antigen under the control of the rat insulin promoter (RIP) [25]. In the absence of Aire, high-affinity antigen-specific CD4 + T cells failed to be deleted in the thymus, implicating that Aire is involved in negative selection of high-affinity autoreactive T cell clones.…”

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confidence: 93%

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

et al. 2006

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“…This helps to establish immune tolerance toward TSA because thymocytes that respond strongly to antigens in the thymus are normally purged from the repertoire or rendered innocuous [2,3]. In the absence of Aire, T cells responsive to Aire-dependent TSA are not tolerized in the thymus, instead escaping to the periphery where they can precipitate the onset of autoimmunity against a wide array of tissues and organs [1,4,5].…”

Section: Introductionmentioning

confidence: 99%

“…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%

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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“…Work using Aire Ϫ/Ϫ mice suggests that Aire upregulates the expression of peripheral tissue-specific genes, including prominent autoantigens such as insulin, in the thymic MECs, a process termed ectopic transcription. In Aire Ϫ/Ϫ mice the presentation of this set of peripheral Ags to developing T cells is disrupted, impairing negative selection and, in a transgenic model, allowing high-affinity autoreactive T cells to mature and migrate to the periphery (6,7). More recently, it was shown that Aire also down-regulates many genes (8,9), and appears to have direct effects on the Ag presentation machinery in the thymic MECs (10).…”

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A Defect of Regulatory T Cells in Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Kekäläinen¹,

Tuovinen²,

Joensuu³

et al. 2007

The Journal of Immunology

190

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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic recessive disease characterized by autoimmunity against multiple tissues, offers a unique possibility to study the breakdown of self-tolerance in humans. It is caused by mutations in the autoimmune regulator gene (AIRE), which encodes a transcriptional regulator. Work using Aire−/− mice suggests that Aire induces ectopic expression of peripheral Ags and promotes their presentation in the thymus. We have explored reasons for the difference between the comparatively mild phenotype of Aire-deficient mice and human APECED patients. We provide evidence that, unlike in the Aire−/− mice, in the patients a key mediator of active tolerance, the CD4+CD25+ regulatory T (Treg) cell subset is impaired. This was shown by significantly decreased expression of FOXP3 mRNA and protein, decreased function, and alterations in TCR repertoire. Also, in the normal human thymus a concentric accumulation of AIRE+ cells was seen around thymic Hassall’s corpuscles, suggesting that in the patients these cells may be involved in the observed Treg cell failure. In Aire−/− mice the expression of FoxP3 was normal and even increased in target tissues in parallel with the lymphocyte infiltration process. Our results suggest that a Treg cell defect is involved in the pathogenesis of APECED and emphasize the importance of active tolerance mechanisms in preventing human autoimmunity.

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Aire regulates negative selection of organ-specific T cells

Cited by 703 publications

References 50 publications

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

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

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

A Defect of Regulatory T Cells in Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

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