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  • Review Article
  • Published:

Transcriptional regulation by AIRE: molecular mechanisms of central tolerance

Nature Reviews Immunology volume 8, pages 948–957 (2008)Cite this article

Key Points

  • Autoimmune regulator (AIRE) protein is mainly expressed by mature medullary thymic epithelial cells, in which it promotes the promiscuous expression of many tissue-specific antigens (TSAs).

  • TSAs that are upregulated by AIRE are presented to developing thymocytes, and this is required for efficient negative selection. Aberrant negative selection in the absence of AIRE leads to the escape of self-reactive thymocytes to the periphery and subsequent autoimmunity.

  • AIRE contains several domains that are characteristic of transcriptional regulators and chromatin-binding proteins, such as a caspase-recruitment domain (CARD), a SP100, AIRE1, NucP41/P75 and DEAF1 (SAND) domain and plant homeodomain (PHD) zinc fingers. Concordantly, many studies have confirmed that AIRE is as a potent transcriptional activator.

  • Several proteins have been found to interact with AIRE, including CREB-binding protein (CBP), protein inhibitor of activated STAT1 (PIAS1), DNA-dependent protein kinase (DNA-PK), histone H3 unmethylated at lysine 4 and the positive transcription elongation factor b (P-TEFb).

  • Interaction with histone H3 that is unmethylated at lysine 4 allows AIRE to bind to certain chromatin regions. At target gene promoters, AIRE promotes transcriptional elongation by binding and recruiting the P-TEFb complex to RNA polymerase II.

  • AIRE-regulated genes tend to cluster in the genome; however, recent findings indicate that at a single-cell level, the expression of TSAs varies, which suggests that gene activation by AIRE can be a stochastic event.

Abstract

The negative selection of T cells in the thymus is necessary for the maintenance of self tolerance. Medullary thymic epithelial cells have a key function in this process as they express a large number of tissue-specific self antigens that are presented to developing T cells. Mutations in the autoimmune regulator (AIRE) protein cause a breakdown of central tolerance that is associated with decreased expression of self antigens in the thymus. In this Review, we discuss the role of AIRE in the thymus and recent advances in our understanding of how AIRE might function at the molecular level to regulate gene expression.

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Figure 1: Schematic representation of the human AIRE protein.
Figure 2: Proposed mechanism of AIRE-mediated gene activation.
Figure 3: Stochastic and coordinated regulation of target genes.

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References

  1. Takahama, Y. Journey through the thymus: stromal guides for T-cell development and selection. Nature Rev. Immunol. 6, 127–135 (2006).

    CAS  Google Scholar 

  2. Anderson, G., Lane, P. J. & Jenkinson, E. J. Generating intrathymic microenvironments to establish T-cell tolerance. Nature Rev. Immunol. 7, 954–963 (2007).

    CAS  Google Scholar 

  3. Derbinski, J. et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202, 33–45 (2005). Using computational analyses of microarray data on medullary RNA transcripts from AIRE-deficient and wild-type mice, references 3 and 96 show that there is a significant degree of clustering of AIRE target genes.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Kyewski, B. & Klein, L. A central role for central tolerance. Annu. Rev. Immunol. 24, 571–606 (2006). This is an excellent review of promiscuous gene expression and the role of AIRE in central tolerance.

    CAS  PubMed  Google Scholar 

  5. Gallegos, A. M. & Bevan, M. J. Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J. Exp. Med. 200, 1039–1049 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Aschenbrenner, K. et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nature Immunol. 8, 351–358 (2007).

    CAS  Google Scholar 

  7. Palmer, E. Negative selection — clearing out the bad apples from the T-cell repertoire. Nature Rev. Immunol. 3, 383–391 (2003).

    CAS  Google Scholar 

  8. Hogquist, K. A., Baldwin, T. A. & Jameson, S. C. Central tolerance: learning self-control in the thymus. Nature Rev. Immunol. 5, 772–782 (2005).

    CAS  Google Scholar 

  9. Yamagata, T., Mathis, D. & Benoist, C. Self-reactivity in thymic double-positive cells commits cells to a CD8 αα lineage with characteristics of innate immune cells. Nature Immunol. 5, 597–605 (2004).

    CAS  Google Scholar 

  10. Nagamine, K. et al. Positional cloning of the APECED gene. Nature Genet. 17, 393–398 (1997).

    CAS  PubMed  Google Scholar 

  11. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nature Genet. 17, 399–403 (1997).

  12. Perheentupa, J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J. Clin. Endocrinol. Metab. 91, 2843–2850 (2006).

    CAS  PubMed  Google Scholar 

  13. Peterson, P. & Peltonen, L. Autoimmune polyendocrinopathy syndrome type 1 (APS1) and AIRE gene: new views on molecular basis of autoimmunity. J. Autoimmun. 25, S49–S55 (2005).

    Google Scholar 

  14. Kuroda, N. et al. Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice. J. Immunol. 174, 1862–1870 (2005). This paper indicates that AIRE regulates the survival of autoreactive T cells beyond the transcriptional control of self-protein expression, for example, by the processing and/or presentation of self proteins.

    CAS  PubMed  Google Scholar 

  15. Ramsey, C. et al. Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum. Mol. Genet. 11, 397–409 (2002).

    CAS  PubMed  Google Scholar 

  16. Niki, S. et al. Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice. J. Clin. Invest. 116, 1292–1301 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Jiang, W., Anderson, M. S., Bronson, R., Mathis, D. & Benoist, C. Modifier loci condition autoimmunity provoked by Aire deficiency. J. Exp. Med. 202, 805–815 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Mathis, D. & Benoist, C. A decade of AIRE. Nature Rev. Immunol. 7, 645–650 (2007). An excellent update on the functional aspects of AIRE in self tolerance.

    CAS  Google Scholar 

  19. Anderson, M. S. et al. Projection of an immunological self shadow within the thymus by the AIRE protein. Science 298, 1395–1401 (2002).

    CAS  PubMed  Google Scholar 

  20. Gavanescu, I., Benoist, C. & Mathis, D. B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: a therapeutic approach for APECED patients. Proc. Natl Acad. Sci. USA 105, 13009–13014 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Devoss, J. J. et al. Effector mechanisms of the autoimmune syndrome in the murine model of autoimmune polyglandular syndrome type 1. J. Immunol. 181, 4072–4079 (2008).

    CAS  PubMed  Google Scholar 

  22. Venanzi, E. S., Melamed, R., Mathis, D. & Benoist, C. The variable immunological self: genetic variation and nongenetic noise in Aire-regulated transcription. Proc. Natl Acad. Sci. USA 105, 15860–15865 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Pontynen, N. et al. Aire deficient mice do not develop the same profile of tissue-specific autoantibodies as APECED patients. J. Autoimmun. 27, 96–104 (2006).

    PubMed  Google Scholar 

  24. Kekalainen, E., Miettinen, A. & Arstila, T. P. Does the deficiency of Aire in mice really resemble human APECED? Nature Rev. Immunol. 7, 1 (2007).

    Google Scholar 

  25. Kont, V. et al. Modulation of Aire regulates the expression of tissue-restricted antigens. Mol. Immunol. 45, 25–33 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Liston, A. et al. Gene dosage — limiting role of Aire in thymic expression, clonal deletion, and organ-specific autoimmunity. J. Exp. Med. 200, 1015–1026 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Liston, A., Lesage, S., Wilson, J., Peltonen, L. & Goodnow, C. C. Aire regulates negative selection of organ-specific T cells. Nature Immunol. 4, 350–354 (2003). This paper shows that AIRE deficiency causes an almost complete failure to delete organ-specific T cells in the thymus.

    CAS  Google Scholar 

  28. Anderson, M. S. et al. The cellular mechanism of Aire control of T cell tolerance. Immunity 23, 227–239 (2005).

    CAS  PubMed  Google Scholar 

  29. Villasenor, J., Benoist, C. & Mathis, D. AIRE and APECED: molecular insights into an autoimmune disease. Immunol. Rev. 204, 156–164 (2005).

    CAS  PubMed  Google Scholar 

  30. DeVoss, J. et al. Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J. Exp. Med. 203, 2727–2735 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Gavanescu, I., Kessler, B., Ploegh, H., Benoist, C. & Mathis, D. Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity. Proc. Natl Acad. Sci. USA 104, 4583–4587 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Sabater, L. et al. Insulin alleles and autoimmune regulator (AIRE) gene expression both influence insulin expression in the thymus. J. Autoimmun. 25, 312–318 (2005).

    CAS  PubMed  Google Scholar 

  33. Giraud, M. et al. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature 448, 934–937 (2007).

    CAS  PubMed  Google Scholar 

  34. Li, J. et al. Developmental pathway of CD4+CD8− medullary thymocytes during mouse ontogeny and its defect in Aire−/– mice. Proc. Natl Acad. Sci. USA 104, 18175–18180 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Heino, M. et al. Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. Biochem. Biophys. Res. Commun. 257, 821–825 (1999).

    CAS  PubMed  Google Scholar 

  36. Zuklys, S. et al. Normal thymic architecture and negative selection are associated with Aire expression, the gene defective in the autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). J. Immunol. 165, 1976–1983 (2000).

    CAS  PubMed  Google Scholar 

  37. Derbinski, J., Schulte, A., Kyewski, B. & Klein, L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nature Immunol. 2, 1032–1039 (2001).

    CAS  Google Scholar 

  38. Gillard, G. O. & Farr, A. G. Contrasting models of promiscuous gene expression by thymic epithelium. J. Exp. Med. 202, 15–19 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Gillard, G. O. & Farr, A. G. Features of medullary thymic epithelium implicate postnatal development in maintaining epithelial heterogeneity and tissue-restricted antigen expression. J. Immunol. 176, 5815–5824 (2006).

    CAS  PubMed  Google Scholar 

  40. Gillard, G. O., Dooley, J., Erickson, M., Peltonen, L. & Farr, A. G. Aire-dependent alterations in medullary thymic epithelium indicate a role for Aire in thymic epithelial differentiation. J. Immunol. 178, 3007–3015 (2007).

    CAS  PubMed  Google Scholar 

  41. Matsumoto, M. Transcriptional regulation in thymic epithelial cells for the establishment of self tolerance. Arch. Immunol. Ther. Exp. (Warsz) 55, 27–34 (2007).

    CAS  Google Scholar 

  42. Meager, A., Peterson, P. & Willcox, N. Hypothetical review: thymic aberrations and type-I interferons; attempts to deduce autoimmunizing mechanisms from unexpected clues in monogenic and paraneoplastic syndromes. Clin. Exp. Immunol. 154, 141–151 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Hanahan, D. Peripheral-antigen-expressing cells in thymic medulla: factors in self-tolerance and autoimmunity. Curr. Opin. Immunol. 10, 656–662 (1998).

    CAS  PubMed  Google Scholar 

  44. Derbinski, J., Pinto, S., Rosch, S., Hexel, K. & Kyewski, B. Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism. Proc. Natl Acad. Sci. USA 105, 657–662 (2008). This paper compares the expression profile of the casein gene locus in mTECs and mammary gland epithelial cells by single-cell PCR.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Gray, D. H. et al. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 108, 3777–3785 (2006).

    CAS  PubMed  Google Scholar 

  46. Gray, D., Abramson, J., Benoist, C. & Mathis, D. Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire. J. Exp. Med. 204, 2521–2528 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Gabler, J., Arnold, J. & Kyewski, B. Promiscuous gene expression and the developmental dynamics of medullary thymic epithelial cells. Eur. J. Immunol. 37, 3363–3372 (2007).

    PubMed  Google Scholar 

  48. Hamazaki, Y. et al. Medullary thymic epithelial cells expressing Aire represent a unique lineage derived from cells expressing claudin. Nature Immunol. 8, 304–311 (2007).

    CAS  Google Scholar 

  49. Dooley, J., Erickson, M. & Farr, A. G. Alterations of the medullary epithelial compartment in the Aire-deficient thymus: implications for programs of thymic epithelial differentiation. J. Immunol. 181, 5225–5232 (2008).

    CAS  PubMed  Google Scholar 

  50. Rossi, S. W. et al. RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J. Exp. Med. 204, 1267–1272 (2007). This study shows that RANKL signals from CD4+CD3− lymphoid tissue inducer cells promote the maturation of RANK-expressing CD80−AIRE− mTEC progenitors into CD80+AIRE+ mTECs.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Akiyama, T. et al. Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 308, 248–251 (2005).

    CAS  PubMed  Google Scholar 

  52. Heino, M. et al. RNA and protein expression of the murine autoimmune regulator gene (Aire) in normal, RelB-deficient and in NOD mouse. Eur. J. Immunol. 30, 1884–1893 (2000).

    CAS  PubMed  Google Scholar 

  53. Kajiura, F. et al. NF-κB-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner. J. Immunol. 172, 2067–2075 (2004).

    CAS  PubMed  Google Scholar 

  54. Zhu, M. et al. NF-κB2 is required for the establishment of central tolerance through an Aire-dependent pathway. J. Clin. Invest. 116, 2964–2971 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Kinoshita, D. et al. Essential role of IκB kinase α in thymic organogenesis required for the establishment of self-tolerance. J. Immunol. 176, 3995–4002 (2006).

    CAS  PubMed  Google Scholar 

  56. Hikosaka, Y. et al. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 29, 438–450 (2008).

    CAS  PubMed  Google Scholar 

  57. White, A. J. et al. Sequential phases in the development of Aire-expressing medullary thymic epithelial cells involve distinct cellular input. Eur. J. Immunol. 38, 942–947 (2008).

    CAS  PubMed  Google Scholar 

  58. Akiyama, T. et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29, 423–437 (2008).

    CAS  PubMed  Google Scholar 

  59. Irla, M. et al. Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity. Immunity 29, 451–463 (2008).

    CAS  PubMed  Google Scholar 

  60. Bloch, D. B. et al. Sp110 localizes to the PML–Sp100 nuclear body and may function as a nuclear hormone receptor transcriptional coactivator. Mol. Cell. Biol. 20, 6138–6146 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Ilmarinen, T. et al. The monopartite nuclear localization signal of autoimmune regulator mediates its nuclear import and interaction with multiple importin α molecules. FEBS J. 273, 315–324 (2006).

    CAS  PubMed  Google Scholar 

  62. Pitkanen, J., Vahamurto, P., Krohn, K. & Peterson, P. Subcellular localization of the autoimmune regulator protein. Characterization of nuclear targeting and transcriptional activation domain. J. Biol. Chem. 276, 19597–19602 (2001).

    CAS  PubMed  Google Scholar 

  63. Pitkanen, J. et al. The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein. J. Biol. Chem. 275, 16802–16809 (2000).

    CAS  PubMed  Google Scholar 

  64. Sanchez-Pulido, L., Valencia, A. & Rojas, A. M. Are promyelocytic leukaemia protein nuclear bodies a scaffold for caspase-2 programmed cell death? Trends Biochem. Sci. 32, 400–406 (2007).

    CAS  PubMed  Google Scholar 

  65. Ferguson, B. J. et al. AIRE's CARD revealed, a new structure for central tolerance provokes transcriptional plasticity. J. Biol. Chem. 283, 1723–1731 (2008).

    CAS  PubMed  Google Scholar 

  66. Ramsey, C., Bukrinsky, A. & Peltonen, L. Systematic mutagenesis of the functional domains of AIRE reveals their role in intracellular targeting. Hum. Mol. Genet. 11, 3299–3308 (2002).

    CAS  PubMed  Google Scholar 

  67. Park, H. H. et al. The death domain superfamily in intracellular signaling of apoptosis and inflammation. Annu. Rev. Immunol. 25, 561–586 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Ilmarinen, T. et al. Functional analysis of SAND mutations in AIRE supports dominant inheritance of the G228W mutation. Hum. Mutat. 26, 322–331 (2005).

    CAS  PubMed  Google Scholar 

  69. Su, M. A. et al. Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire. J. Clin. Invest. 118, 1712–1726 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Cetani, F. et al. A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis. J. Clin. Endocrinol. Metab. 86, 4747–4752 (2001).

    CAS  PubMed  Google Scholar 

  71. Bottomley, M. J. et al. NMR structure of the first PHD finger of autoimmune regulator protein (AIRE1). Insights into autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) disease. J. Biol. Chem. 280, 11505–11512 (2005).

    CAS  PubMed  Google Scholar 

  72. Bjorses, P. et al. Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein. Am. J. Hum. Genet. 66, 378–392 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Meloni, A., Incani, F., Corda, D., Cao, A. & Rosatelli, M. C. Role of PHD fingers and COOH-terminal 30 amino acids in AIRE transactivation activity. Mol. Immunol. 45, 805–809 (2008).

    CAS  PubMed  Google Scholar 

  74. Halonen, M. et al. APECED-causing mutations in AIRE reveal the functional domains of the protein. Hum. Mutat. 23, 245–257 (2004).

    CAS  PubMed  Google Scholar 

  75. Uchida, D. et al. AIRE functions as an E3 ubiquitin ligase. J. Exp. Med. 199, 167–172 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Savkur, R. S. & Burris, T. P. The coactivator LXXLL nuclear receptor recognition motif. J. Pept. Res. 63, 207–212 (2004).

    CAS  PubMed  Google Scholar 

  77. Helton, E. S., Zhang, J. & Chen, X. The proline-rich domain in p63 is necessary for the transcriptional and apoptosis-inducing activities of TAp63. Oncogene 27, 2843–2850 (2008).

    CAS  PubMed  Google Scholar 

  78. Mittaz, L. et al. Isolation and characterization of the mouse Aire gene. Biochem. Biophys. Res. Commun. 255, 483–490 (1999).

    CAS  PubMed  Google Scholar 

  79. Saltis, M. et al. Evolutionarily conserved and divergent regions of the autoimmune regulator (Aire) gene: a comparative analysis. Immunogenetics 60, 105–114 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Bjorses, P. et al. Localization of the APECED protein in distinct nuclear structures. Hum. Mol. Genet. 8, 259–266 (1999).

    CAS  PubMed  Google Scholar 

  81. Kumar, P. G. et al. The autoimmune regulator (AIRE) is a DNA-binding protein. J. Biol. Chem. 276, 41357–41364 (2001).

    CAS  PubMed  Google Scholar 

  82. Rinderle, C., Christensen, H. M., Schweiger, S., Lehrach, H. & Yaspo, M. L. AIRE encodes a nuclear protein co-localizing with cytoskeletal filaments: altered sub-cellular distribution of mutants lacking the PHD zinc fingers. Hum. Mol. Genet. 8, 277–290 (1999).

    CAS  PubMed  Google Scholar 

  83. Bernardi, R. & Pandolfi, P. P. Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nature Rev. Mol. Cell Biol. 8, 1006–1016 (2007).

    CAS  Google Scholar 

  84. Shiels, C. et al. PML bodies associate specifically with the MHC gene cluster in interphase nuclei. J. Cell Sci. 114, 3705–3716 (2001).

    CAS  PubMed  Google Scholar 

  85. Kumar, P. P. et al. Functional interaction between PML and SATB1 regulates chromatin-loop architecture and transcription of the MHC class I locus. Nature Cell Biol. 9, 45–56 (2007).

    PubMed  Google Scholar 

  86. Akiyoshi, H. et al. Subcellular expression of autoimmune regulator is organized in a spatiotemporal manner. J. Biol. Chem. 279, 33984–33991 (2004).

    CAS  PubMed  Google Scholar 

  87. Tao, Y. et al. AIRE recruits multiple transcriptional components to specific genomic regions through tethering to nuclear matrix. Mol. Immunol. 43, 335–345 (2006).

    CAS  PubMed  Google Scholar 

  88. Pitkanen, J. et al. Cooperative activation of transcription by autoimmune regulator AIRE and CBP. Biochem. Biophys. Res. Commun. 333, 944–953 (2005).

    CAS  PubMed  Google Scholar 

  89. Liiv, I. et al. DNA-PK contributes to the phosphorylation of AIRE: importance in transcriptional activity. Biochim. Biophys. Acta 1783, 74–83 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Björses, P. et al. Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein. Am. J. Hum. Genet. 66, 378–392 (2000).

    Google Scholar 

  91. Oven, I. et al. AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells. Mol. Cell. Biol. 27, 8815–8823 (2007). In this study, it was found that AIRE regulates transcriptional elongation by binding and recruiting the P-TEFb complex to target promoters in a medullary thymic epithelial cell line.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Purohit, S., Kumar, P. G., Laloraya, M. & She, J. X. Mapping DNA-binding domains of the autoimmune regulator protein. Biochem. Biophys. Res. Commun. 327, 939–944 (2005).

    CAS  PubMed  Google Scholar 

  93. Ruan, Q. G. et al. The autoimmune regulator directly controls the expression of genes critical for thymic epithelial function. J. Immunol. 178, 7173–7180 (2007).

    CAS  PubMed  Google Scholar 

  94. Surdo, P. L., Bottomley, M. J., Sattler, M. & Scheffzek, K. Crystal structure and nuclear magnetic resonance analyses of the SAND domain from glucocorticoid modulatory element binding protein-1 reveals deoxyribonucleic acid and zinc binding regions. Mol. Endocrinol. 17, 1283–1295 (2003).

    PubMed  Google Scholar 

  95. Bottomley, M. J. et al. The SAND domain structure defines a novel DNA-binding fold in transcriptional regulation. Nature Struct. Biol. 8, 626–633 (2001).

    CAS  PubMed  Google Scholar 

  96. Johnnidis, J. B. et al. Chromosomal clustering of genes controlled by the AIRE transcription factor. Proc. Natl Acad. Sci. USA 102, 7233–7238 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Kalkhoven, E. CBP and p300: HATs for different occasions. Biochem. Pharmacol. 68, 1145–1155 (2004).

    CAS  PubMed  Google Scholar 

  98. Ilmarinen, T. et al. Functional interaction of AIRE with PIAS1 in transcriptional regulation. Mol. Immunol. 45, 1847–1862 (2008).

    CAS  PubMed  Google Scholar 

  99. Mauldin, S. K., Getts, R. C., Liu, W. & Stamato, T. D. DNA-PK-dependent binding of DNA ends to plasmids containing nuclear matrix attachment region DNA sequences: evidence for assembly of a repair complex. Nucleic Acids Res. 30, 4075–4087 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Okubo, S. et al. NMR structure of the N-terminal domain of SUMO ligase PIAS1 and its interaction with tumor suppressor p53 and A/T-rich DNA oligomers. J. Biol. Chem. 279, 31455–31461 (2004).

    CAS  PubMed  Google Scholar 

  101. Galande, S., Purbey, P. K., Notani, D. & Kumar, P. P. The third dimension of gene regulation: organization of dynamic chromatin loopscape by SATB1. Curr. Opin. Genet. Dev. 17, 408–414 (2007).

    CAS  PubMed  Google Scholar 

  102. Razin, S. V. et al. Chromatin domains and regulation of transcription. J. Mol. Biol. 369, 597–607 (2007).

    CAS  PubMed  Google Scholar 

  103. Bres, V., Yoh, S. M. & Jones, K. A. The multi-tasking P–TEFb complex. Curr. Opin. Cell Biol. 20, 334–340 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Mellor, J. It takes a PHD to read the histone code. Cell 126, 22–24 (2006).

    CAS  PubMed  Google Scholar 

  105. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    CAS  PubMed  Google Scholar 

  106. Org, T. et al. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep. 9, 370–376 (2008). This study showed that AIRE interacts selectively with histone H3 through its first PHD zinc finger and preferentially binds to unmethylated histone H3 lysine 4.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Koh, A. S. et al. Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity. Proc. Natl Acad. Sci. USA 105, 15878–15883 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Zhao, X. D. et al. Whole-genome mapping of histone h3 lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells. Cell Stem Cell 1, 286–298 (2007).

    CAS  PubMed  Google Scholar 

  110. Sato, K. et al. Aire downregulates multiple molecules that have contradicting immune-enhancing and immune-suppressive functions. Biochem. Biophys. Res. Commun. 318, 935–940 (2004).

    CAS  PubMed  Google Scholar 

  111. Gotter, J., Brors, B., Hergenhahn, M. & Kyewski, B. Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters. J. Exp. Med. 199, 155–166 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Kaufmann, B. B. & van Oudenaarden, A. Stochastic gene expression: from single molecules to the proteome. Curr. Opin. Genet. Dev. 17, 107–112 (2007).

    CAS  PubMed  Google Scholar 

  113. Carninci, P. et al. The transcriptional landscape of the mammalian genome. Science 309, 1559–1563 (2005).

    CAS  PubMed  Google Scholar 

  114. Blake, W. J., KÆrn, M., Cantor, C. R. & Collins, J. J. Noise in eukaryotic gene expression. Nature 422, 633–637 (2003).

    CAS  PubMed  Google Scholar 

  115. Komili, S. & Silver, P. A. Coupling and coordination in gene expression processes: a systems biology view. Nature Rev. Genet. 9, 38–48 (2008).

    CAS  PubMed  Google Scholar 

  116. Misteli, T. Beyond the sequence: cellular organization of genome function. Cell 128, 787–800 (2007).

    CAS  PubMed  Google Scholar 

  117. Villasenor, J., Besse, W., Benoist, C. & Mathis, D. Ectopic expression of peripheral-tissue antigens in the thymic epithelium: probabilistic, monoallelic, misinitiated. Proc. Natl Acad. Sci. USA 105, 15854–15859 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Bar-Even, A. et al. Noise in protein expression scales with natural protein abundance. Nature Genet. 38, 636–643 (2006).

    CAS  PubMed  Google Scholar 

  119. Raj, A., Peskin, C. S., Tranchina, D., Vargas, D. Y. & Tyagi, S. Stochastic mRNA synthesis in mammalian cells. PLoS Biol. 4, e309 (2006).

    PubMed  PubMed Central  Google Scholar 

  120. Pombo, A. & Branco, M. R. Functional organisation of the genome during interphase. Curr. Opin. Genet. Dev. 17, 451–455 (2007).

    CAS  PubMed  Google Scholar 

  121. Sillanpaa, N. et al. Autoimmune regulator induced changes in the gene expression profile of human monocyte-dendritic cell-lineage. Mol. Immunol. 41, 1185–1198 (2004).

    CAS  PubMed  Google Scholar 

  122. Gardner, J. M. et al. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science 321, 843–847 (2008). This paper reports the identification of extrathymic AIRE-expressing cells in the secondary lymphoid organs.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Cheng, M. H., Shum, A. K. & Anderson, M. S. What's new in the Aire? Trends Immunol. 28, 321–327 (2007).

    CAS  PubMed  Google Scholar 

  124. Alimohammadi, M. et al. Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen. N. Engl. J. Med. 358, 1018–1028 (2008).

    CAS  PubMed  Google Scholar 

  125. Meager, A. et al. Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med. 3, e289 (2006).

    PubMed  PubMed Central  Google Scholar 

  126. Kisand, K. et al. Interferon autoantibodies associated with AIRE deficiency decrease the expression of IFN-stimulated genes. Blood 112, 2657–2666 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Strobel, P. et al. Deficiency of the autoimmune regulator AIRE in thymomas is insufficient to elicit autoimmune polyendocrinopathy syndrome type 1 (APS-1). J. Pathol. 211, 563–571 (2007).

    CAS  PubMed  Google Scholar 

  128. Mestas, J. & Hughes, C. C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).

    CAS  PubMed  Google Scholar 

  129. Nagafuchi, S. et al. Mitogen-activated protein kinase pathway controls autoimmune regulator (AIRE) gene expression in granulo-monocyte colony stimulating factor (GM-CSF)-stimulated myelomonocytic leukemia OTC-4 cells. Immunol. Lett. 99, 130–135 (2005).

    CAS  PubMed  Google Scholar 

  130. Kogawa, K. et al. Expression of AIRE gene in peripheral monocyte/dendritic cell lineage. Immunol. Lett. 80, 195–198 (2002).

    CAS  PubMed  Google Scholar 

  131. Suzuki, E. et al. Expression of AIRE in thymocytes and peripheral lymphocytes. Autoimmunity 41, 133–139 (2008).

    CAS  PubMed  Google Scholar 

  132. Schaller, C. E. et al. Expression of Aire and the early wave of apoptosis in spermatogenesis. J. Immunol. 180, 1338–1343 (2008).

    CAS  PubMed  Google Scholar 

  133. Hubert, F. X. et al. A specific anti-Aire antibody reveals Aire expression is restricted to medullary thymic epithelial cells and not expressed in periphery. J. Immunol. 180, 3824–3832 (2008).

    CAS  PubMed  Google Scholar 

  134. Hassler, S. et al. Aire-deficient mice develop hematopoetic irregularities and marginal zone B-cell lymphoma. Blood 108, 1941–1948 (2006).

    PubMed  Google Scholar 

  135. Ramsey, C. et al. Increased antigen presenting cell-mediated T cell activation in mice and patients without the autoimmune regulator. Eur. J. Immunol. 36, 305–317 (2006).

    CAS  PubMed  Google Scholar 

  136. Pontynen, N. et al. Critical immunological pathways are downregulated in APECED patient dendritic cells. J. Mol. Med. 86, 1139–1152 (2008).

    CAS  PubMed  Google Scholar 

  137. Lee, J. W. et al. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nature Immunol. 8, 181–190 (2007).

    CAS  Google Scholar 

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Acknowledgements

We would like to thank all laboratory members and many colleagues including M. Anderson, G. Holländer, K. Krohn, O. Kämpe, B. Kyewski, A. Marx, M. Matsumoto, G. Musco, T. Rich, H. Scott, I. Ulmanen and N. Willcox for useful discussions. This work was supported by EU FP6 project Thymaide, The Wellcome Trust, European Regional Development Fund and Estonian Science Foundation.

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  1. Institute of General and Molecular Pathology, University of Tartu, Ravila 19, Biomedicum, 5O411, Tartu, Estonia

    Pärt Peterson, Tõnis Org & Ana Rebane

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DATABASES

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EurAPS

Glossary

Central tolerance

The lack of self responsiveness that occurs during lymphocyte development in the central lymphoid organs. B-cell progenitors in the bone marrow and T-cell progenitors in the thymus that strongly recognize self antigen either undergo further rearrangement of antigen-receptor genes to avoid reactivity to self or face deletion by apoptosis.

Negative selection

The deletion of self-reactive thymocytes in the thymus. Thymocytes expressing T-cell receptors that strongly recognize self peptide bound to self MHC molecules undergo apoptosis in response to the signalling that is generated by high-affinity binding of their target antigen presented by cells in the thymic medulla.

Penetrance

The proportion of affected individuals among carriers of a particular genotype. If all individuals with a disease genotype have the disease phenotype, then the disease is said to be completely penetrant.

Söjgren's syndrome

An organ-specific autoimmune disorder that is characterized by lymphocytic infiltrates, tissue destruction and functional decline of salivary or lacrimal glands, and the systemic production of autoantibodies specific for ribonucleoproteins.

Non-obese diabetic (NOD) mice

NOD mice develop spontaneous diabetes, including the development of islet-specific autoantibodies and inflammation of the pancreatic islets.

Tight junction

A belt-like region of adhesion between adjacent epithelial or endothelial cells that regulates paracellular flux. Tight-junction proteins include the integral membrane proteins occludin and claudin, in association with cytoplasmic zonula occludens proteins.

Caspase-recruitment domain

A protein domain that is found in certain initiator caspases (for example, mammalian caspase 9) and their adaptor proteins (for example, APAF1) that function in inflammation and apoptosis. This domain mediates protein–protein interactions.

PHD zinc finger

A domain that consists of about 60 amino acids and are characterized by a C4HC3 (four cysteines, one histidine, three cysteines) signature that binds two zinc ions. It has been shown recently to bind to histone H3 modified or unmodified at specific residues.

Nuclear bodies

Structurally and functionally heterogeneous subnuclear structures (0.2–1μm) that are present in most mammalian cells and that have been implicated in cellular senescence, apoptosis, proliferation and maintenance of genomic stability through transcriptional repression, transcriptional activation and protein degradation.

Nuclear speckles

Dynamic subnuclear structures that contain pre-mRNA splicing factors and other proteins that are involved in transcription, 3′-end RNA processing and reversible protein phosphorylation.

Nuclear matrix

A network of nuclear proteins that provides a structural framework for chromatin organization.

Enhancer

A region of DNA that can bind activator proteins, which can initiate the transcription of a gene promoter that is a long distance from the enhancer.

Insulator

A boundary element in the genome that can block the activity of nearby enhancer regions or function as a barrier against heterochromatin spreading into active chromatin areas.

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Peterson, P., Org, T. & Rebane, A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat Rev Immunol 8, 948–957 (2008). https://doi.org/10.1038/nri2450

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