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This work shows that the transcription of Aire-regulated TSAs is somewhat noisy and variable between mouse breeds and even within individuals.
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This study shows that mTECs can induce the positive selection of FoxP3-expressing T regulatory cells in a T cell receptor transgenic model.
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Aschenbrenner K., D'Cruz L.M., Vollmann E.H., Hinterberger M., Emmerich J., Swee L.K., Rolink A., and Klein L. Selection of Foxp3+ regulatory T cells specific for self-antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol 8 (2007) 351-358. This study shows that mTECs can induce the positive selection of FoxP3-expressing T regulatory cells in a T cell receptor transgenic model.
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The autoimmune regulator directly controls the expression of genes critical for thymic epithelial function
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23
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Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels
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Derbinski J., Gabler J., Brors B., Tierling S., Jonnakuty S., Hergenhahn M., Peltonen L., Walter J., and Kyewski B. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med 202 (2005) 33-45
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24
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Johnnidis, J.B.1
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25
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27944494841
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AIRE recruits multiple transcriptional components to specific genomic regions through tethering to nuclear matrix
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Tao Y., Kupfer R., Stewart B.J., Williams-Skipp C., Crowell C.K., Patel D.D., Sain S., and Scheinman R.I. AIRE recruits multiple transcriptional components to specific genomic regions through tethering to nuclear matrix. Mol Immunol 43 (2006) 335-345
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Tao, Y.1
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This study describes a dominant-negative allele of Aire harboring a point mutation in the SAND domain, and highlights the importance of quantitative changes in thymic TSA expression in autoimmunity.
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Su M.A., Giang K., Zumer K., Jiang H., Oven I., Rinn J.L., Devoss J.J., Johannes K.P., Lu W., Gardner J., et al. Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire. J Clin Invest 118 (2008) 1712-1726. This study describes a dominant-negative allele of Aire harboring a point mutation in the SAND domain, and highlights the importance of quantitative changes in thymic TSA expression in autoimmunity.
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38649131259
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Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism
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By studying promiscuous gene expression at a single-cell level, these authors show that TSA transcription is more likely to be stochastic rather than developmentally driven.
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Derbinski J., Pinto S., Rosch S., Hexel K., and Kyewski B. Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism. Proc Natl Acad Sci U S A 105 (2008) 657-662. By studying promiscuous gene expression at a single-cell level, these authors show that TSA transcription is more likely to be stochastic rather than developmentally driven.
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Derbinski, J.1
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0038824426
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The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein
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Pitkanen J., Doucas V., Sternsdorf T., Nakajima T., Aratani S., Jensen K., Will H., Vahamurto P., Ollila J., Vihinen M., et al. The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein. J Biol Chem 275 (2000) 16802-16809
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AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells
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These authors show that AIRE can participate in transcriptional elongation and suggest that this may be part of the mechanism by which AIRE drives transcription of such a broad array of target genes.
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Oven I., Brdickova N., Kohoutek J., Vaupotic T., Narat M., and Peterlin B.M. AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells. Mol Cell Biol 27 (2007) 8815-8823. These authors show that AIRE can participate in transcriptional elongation and suggest that this may be part of the mechanism by which AIRE drives transcription of such a broad array of target genes.
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DNA-PK contributes to the phosphorylation of AIRE: importance in transcriptional activity
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Saltis M., Criscitiello M.F., Ohta Y., Keefe M., Trede N.S., Goitsuka R., and Flajnik M.F. Evolutionarily conserved and divergent regions of the autoimmune regulator (Aire) gene: a comparative analysis. Immunogenetics 60 (2008) 105-114
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Halonen M., Kangas H., Ruppell T., Ilmarinen T., Ollila J., Kolmer M., Vihinen M., Palvimo J., Saarela J., Ulmanen I., et al. APECED-causing mutations in AIRE reveal the functional domains of the protein. Hum Mutat 23 (2004) 245-257
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The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression
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(See below, reference [34]).
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Org T., Chignola F., Hetenyi C., Gaetani M., Rebane A., Liiv I., Maran U., Mollica L., Bottomley M.J., Musco G., et al. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep 9 (2008) 370-376. (See below, reference [34]).
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These two studies show that a PHD finger domain of AIRE specifically interacts with histone H3 unmethylated at lysine 4, suggesting an epigenetic link to the mechanism of AIRE's transcriptional activity.
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Proliferative arrest and rapid turnover of thymic epithelial cells expressin Aire
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By studying the proliferative activity and turnover of mTEC subpopulations, these authors conclude that Aire-expressing mTECs represent a terminally differentiated population that goes through programmed cell death under the influence of AIRE.
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By creating an Aire-reporter line of mice expressing GFP under the control of the Aire locus, these authors suggest that AIRE influences the proper development of the thymic medulla.
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Yano M., Kuroda N., Han H., Meguro-Horike M., Nishikawa Y., Kiyonari H., Maemura K., Yanagawa Y., Obata K., Takahashi S., et al. Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance. J Exp Med 205 (2008) 2827-2838. By creating an Aire-reporter line of mice expressing GFP under the control of the Aire locus, these authors suggest that AIRE influences the proper development of the thymic medulla.
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The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator
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These three reports offer a detailed study of the developmental pathways that control the proper development of Aire-expressing mTECs including roles for RANK, CD40, and negative selection in this process.
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Irla M., Hugues S., Gill J., Nitta T., Hikosaka T., Williams I.R., Hubert F.-X., Scott H.S., Takahama Y., Hollander G.A., et al. Autoantigen-specific interactions with cd4+ thymocytes control mature medullary thymic epithelial cell cellularity. Immunity 29 (2008) 451-463. These three reports offer a detailed study of the developmental pathways that control the proper development of Aire-expressing mTECs including roles for RANK, CD40, and negative selection in this process.
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Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self
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Here, LNSCs were shown to ectopically express transgenic intestine-derived TSA to CD8+ T cells, inducing deletional tolerance. This paper was the first to show that lymph node stroma expresses mRNA for Aire and for a variety of TSAs.
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Lee J.W., Epardaud M., Sun J., Becker J.E., Cheng A.C., Yonekura A.R., Heath J.K., and Turley S.J. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat Immunol 8 (2007) 181-190. Here, LNSCs were shown to ectopically express transgenic intestine-derived TSA to CD8+ T cells, inducing deletional tolerance. This paper was the first to show that lymph node stroma expresses mRNA for Aire and for a variety of TSAs.
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This paper identifies a tolerogenic stromal population in secondary lymphoid organs that expresses Aire and an array of AIRE-regulated TSAs distinct from the thymic AIRE-regulated repertoire.
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Gardner J.M., Devoss J.J., Friedman R.S., Wong D.J., Tan Y.X., Zhou X., Johannes K.P., Su M.A., Chang H.Y., Krummel M.F., et al. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science 321 (2008) 843-847. This paper identifies a tolerogenic stromal population in secondary lymphoid organs that expresses Aire and an array of AIRE-regulated TSAs distinct from the thymic AIRE-regulated repertoire.
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Deletional self-tolerance to a melanocyte/melanoma antigen derived from tyrosinase is mediated by a radio-resistant cell in peripheral and mesenteric lymph nodes
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This paper demonstrates that a radioresistant cell population in the peripheral lymphoid organs ectopically expresses endogenous self-antigen and can mediate deletional tolerance against that antigen.
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Nichols L.A., Chen Y., Colella T.A., Bennett C.L., Clausen B.E., and Engelhard V.H. Deletional self-tolerance to a melanocyte/melanoma antigen derived from tyrosinase is mediated by a radio-resistant cell in peripheral and mesenteric lymph nodes. J Immunol 179 (2007) 993-1003. This paper demonstrates that a radioresistant cell population in the peripheral lymphoid organs ectopically expresses endogenous self-antigen and can mediate deletional tolerance against that antigen.
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These authors utilize an inducible Aire-expressing transgenic mouse to determine when the timing of Aire expression is crucial for the induction of tolerance and suggest that the crucial window is in the perinatal period.
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