The Thymus as a Mirror of the Body’s Gene Expression

  • Geraldo A. PassosEmail author
  • Adriana B. Genari
  • Amanda F. Assis
  • Ana C. Monteleone-Cassiano
  • Eduardo A. Donadi
  • Ernna H. Oliveira
  • Max J. Duarte
  • Mayara V. Machado
  • Pedro P. Tanaka
  • Romário Mascarenhas


The thymus is a complex organ formed by different cell types that establish close interaction. The role played by the thymic stroma is very intriguing, since it is not only a connective tissue or a support structure. The stromal thymic epithelial cells (TECs), establish physical and functional interaction with developing thymocytes culminating in a unique function of this organ, the induction of central tolerance. The role played by the medullary thymic epithelial cells (mTECs) is noteworthy and is being the focus of many studies. The transcriptome of mTEC cells is also very complex. These cells express nearly the entire functional genome without altering their morphological and functional features. Among thousand mRNAs expressed, a particular set encodes together all peripheral tissue antigens (PTAs), which represent the different tissues and organs of the body. The consequence of ectopic proteins translated from these mRNAs in the thymus is immunological and is associated with self-non-self discrimination and induction of central tolerance. Due to the wide variety of PTAs, this process was termed promiscuous gene expression (PGE), whose control is shared between autoimmune regulator (human AIRE/murine Aire), a transcriptional modulator and forebrain-expressed zinc finger 2 (FEZF2/Fezf2), a transcription factor. Therefore, this molecular-genetic process is closely linked to the elimination of autoreactive thymocytes in the thymus through negative selection. In this chapter, we review PGE in mTECs and its immunologic implication, the role of the Aire and Fezf2 genes, the role of Aire on the expression of miRNAs in mTECs, its consequence on PGE and the manipulation of the Aire expression either by siRNA or by genome editing using the Crispr-Cas9 system.



We thank São Paulo Research Foundation (FAPESP), São Paulo, Brazil, through grant 13/17481-1 and 17/10780-4 to GAP, National Council for Scientific and Technological Development (CNPq), Brasília, Brazil, through grant 305787/2017-9 to GAP and grant 304931/2014-1 to EAD. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)—Brazil—Financial code 001. We also thank Ms Janine Bottosso Passos for the Figs. 9.2 and 9.3.


  1. Aaltonen J, Björses P, Sandkuijl L, Perheentupa J, Peltonen L (1994) An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21. Nat Genet 8:83–87CrossRefPubMedPubMedCentralGoogle Scholar
  2. Abramson J, Anderson G (2017) Thymic epithelial cells. Annu Rev Immunol 35:85–118PubMedCrossRefPubMedCentralGoogle Scholar
  3. Abramson J, Goldfarb Y (2016) AIRE: from promiscuous molecular partnerships to promiscuous gene expression. Eur J Immunol 46:22–33PubMedPubMedCentralCrossRefGoogle Scholar
  4. Aichinger M, Wu C, Nedjic J, Klein L (2013) Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance. J Exp Med 210:287–300PubMedPubMedCentralCrossRefGoogle Scholar
  5. Anderson MS, Su MA (2016) AIRE expands: new roles in immune tolerance and beyond. Nat Rev Immunol 16:247–258PubMedPubMedCentralCrossRefGoogle Scholar
  6. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D (2002) Projection of an immunological self shadow within the thymus by the aire protein. Science 298:1395–1401CrossRefPubMedPubMedCentralGoogle Scholar
  7. Anderson G, Lane PJ, Jenkinson EJ (2007) Generating intrathymic microenvironments to establish T-cell tolerance. Nat Rev Immunol 7:954–963PubMedCrossRefPubMedCentralGoogle Scholar
  8. Aschenbrenner K, D’Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee LK, Rolink A, Klein L (2007) Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol 8:351–358PubMedCrossRefPubMedCentralGoogle Scholar
  9. Assis AF, Oliveira EH, Donate PB, Giuliatti S, Nguyen C, Passos GA (2014) What is the transcriptome and how it is evaluated? In: Passos GA (ed) Transcriptomics in health and disease. Springer International Publishing, Switzerland, pp 3–48Google Scholar
  10. Assis AF, Li J, Donate PB, Dernowsek JA, Manley NR, Passos GA (2018) Predicted miRNA-mRNA-mediated posttranscriptional control associated with differences in cervical and thoracic thymus function. Mol Immunol 99:39–52PubMedCrossRefPubMedCentralGoogle Scholar
  11. Bansal K, Yoshida H, Benoist C, Mathis D (2017) The transcriptional regulator Aire binds and activates super-enhancers. Nat Immunol 18:63–273CrossRefGoogle Scholar
  12. Björses P, Aaltonen J, Horelli-Kuitunen N, Yaspo ML, Peltonen L (1998) Gene defect behind APECED: a new clue to autoimmunity. Hum Mol Genet 7:1547–1553PubMedCrossRefPubMedCentralGoogle Scholar
  13. Bogu GA, Vizan P, Stanton LW, Beato M, Di Croce L, Marti-Renom MA (2015) Chromatin and RNA maps reveal regulatory long noncoding RNAs in mouse. Mol Cell Biol 36:809–819PubMedCrossRefPubMedCentralGoogle Scholar
  14. Brennecke P, Reyes A, Pinto S, Rattay K, Nguyen M, Küchler R, Huber W, Kyewski B, Steinmetz LM (2015) Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells. Nat Immunol 16:933–941PubMedPubMedCentralCrossRefGoogle Scholar
  15. Chen LL, Carmichael GG (2010) Long noncoding RNAs in mammalian cells: what, where, and why? Wiley Interdiscip Rev RNA 1:2–21PubMedCrossRefPubMedCentralGoogle Scholar
  16. Chen J, Yang W, Yu C, Li Y (2008) Autoimmune regulator initiates the expression of promiscuous genes in thymic epithelial cells. Immunol Investig 37:203–214CrossRefGoogle Scholar
  17. Chen P, Zhang H, Sun X, Hu Y, Jiang W, Liu Z, Liu S, Zhang X (2017) microRNA-449a modulates medullary thymic epithelial cell differentiation. Sci Rep 7:15915PubMedPubMedCentralCrossRefGoogle Scholar
  18. Danan-Gotthold M, Guyon C, Giraud M, Levanon EY, Abramson J (2016) Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells. Genome Biol 17:219PubMedPubMedCentralCrossRefGoogle Scholar
  19. Delás MJ, Hannon GJ (2017) lncRNAs in development and disease: from functions to mechanisms. Open Biol 7(7):170121PubMedPubMedCentralCrossRefGoogle Scholar
  20. Derbinski J, Kyewski B (2010) How thymic antigen presenting cells sample the body’s self-antigens. Curr Opin Immunol 22:592–600PubMedPubMedCentralCrossRefGoogle Scholar
  21. Derbinski J, Schulte A, Kyewski B, Klein L (2001) Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2:1032–1039CrossRefPubMedPubMedCentralGoogle Scholar
  22. Derbinski J, Gäbler J, Brors B, Tierling S, Jonnakuty S, Hergenhahn M, Peltonen L, Walter J, Kyewski B (2005) Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med 202:33–45PubMedPubMedCentralCrossRefGoogle Scholar
  23. Derbinski J, Pinto S, Rösch S, Hexel K, Kyewski B (2008) Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism. Proc Natl Acad Sci U S A 105:657–662PubMedPubMedCentralCrossRefGoogle Scholar
  24. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A (2012a) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 22:1775–1789PubMedPubMedCentralCrossRefGoogle Scholar
  25. Derrien T, Guigó R, Johnson R (2012b) The long non-coding RNAs: a new (p)layer in the “dark matter”. Front Genet 2:107PubMedPubMedCentralCrossRefGoogle Scholar
  26. Donate PB, Fornari TA, Junta CM, Magalhães DA, Macedo C, Cunha TM, Nguyen C, Cunha FQ, Passos GA (2011) Collagen induced arthritis (CIA) in mice features regulatory transcriptional network connecting major histocompatibility complex (MHC H2) with autoantigen genes in the thymus. Immunobiology 2016:591–603CrossRefGoogle Scholar
  27. Dooley J, Liston A (2012) Molecular control over thymic involution: from cytokines and microRNA to aging and adipose tissue. Eur J Immunol 42:1073–1079PubMedCrossRefPubMedCentralGoogle Scholar
  28. Dooley J, Erickson M, Gillard GO, Farr AG (2006) Cervical thymus in the mouse. J Immunol 176:6484–6490PubMedCrossRefPubMedCentralGoogle Scholar
  29. Fang Y, Fullwood MJ (2016) Roles, functions, and mechanisms of long non-coding RNAs in cancer. Genomics Proteomics Bioinformatics 14:42–54PubMedPubMedCentralCrossRefGoogle Scholar
  30. Fornari TA, Donate PB, Macedo C, Sakamoto-Hojo ET, Donadi EA, Passos GA (2011) Development of type 1 diabetes mellitus in nonobese diabetic mice follows changes in thymocyte and peripheral T lymphocyte transcriptional activity. Clin Dev Immunol 2011:158735PubMedPubMedCentralCrossRefGoogle Scholar
  31. Fornari TA, Donate PB, Assis AF, Macedo C, Sakamoto-Hojo ET, Donadi EA, Passos GA (2015) Comprehensive survey of miRNA-mRNA interactions reveals that Ccr7 and Cd247 (CD3 zeta) are posttranscriptionally controlled in pancreas infiltrating T lymphocytes of non-obese diabetic (NOD) mice. PLoS One 10:e0142688PubMedPubMedCentralCrossRefGoogle Scholar
  32. Fuller PJ, Verity K (1989) Somatostatin gene expression in the thymus gland. J Immunol 143:1015–1017PubMedPubMedCentralGoogle Scholar
  33. Gäbler J, Arnold J, Kyewski B (2007) Promiscuous gene expression and the developmental dynamics of medullary thymic epithelial cells. Eur J Immunol 37:3363–3372PubMedCrossRefPubMedCentralGoogle Scholar
  34. Gallegos AM, Bevan MJ (2004) Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J Exp Med 200:1039–1049PubMedPubMedCentralCrossRefGoogle Scholar
  35. Geenen V, Legros JJ, Franchimont P, Baudrihaye M, Defresne MP, Boniver J (1986) The neuroendocrine thymus: coexistence of oxytocin and neurophysin in the human thymus. Science 232:508–511PubMedCrossRefPubMedCentralGoogle Scholar
  36. Giraud M, Yoshida H, Abramson J, Rahl PB, Young RA, Mathis D, Benoist C (2012) Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells. Proc Natl Acad Sci U S A 109:535–540PubMedCrossRefPubMedCentralGoogle Scholar
  37. Gotter J, Brors B, Hergenhahn M, Kyewski B (2004) Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters. J Exp Med 199:155–166PubMedPubMedCentralCrossRefGoogle Scholar
  38. Gray DH, Fletcher AL, Hammett M, Seach N, Ueno T, Young LF, Barbuto J, Boyd RL, Chidgey AP (2008) Unbiased analysis, enrichment and purification of thymic stromal cells. J Immunol Methods 329:56–66PubMedCrossRefPubMedCentralGoogle Scholar
  39. Groettrup M, Kirk CJ, Basler M (2010) Proteasomes in immune cells: more than peptide producers? Nat Rev Immunol 10:73–77PubMedCrossRefPubMedCentralGoogle Scholar
  40. Halkias J, Melichar HJ, Taylor KT, Ross JO, Yen B, Cooper SB, Winoto A, Robey EA (2013) Opposing chemokine gradients control human thymocyte migration in situ. J Clin Invest 123:2131–2142PubMedPubMedCentralCrossRefGoogle Scholar
  41. Han VK, D’Ercole AJ, Lund PK (1987) Cellular localization of somatomedin (insulin-like growth factor) messenger RNA in the human fetus. Science 236:19319–19317CrossRefGoogle Scholar
  42. Hanahan D (1998) Peripheral-antigen-expressing cells in thymic medulla: factors in self-tolerance and autoimmunity. Curr Opin Immunol 10:656–662PubMedCrossRefPubMedCentralGoogle Scholar
  43. Hasegawa H, Matsumoto T (2018) Mechanisms of tolerance induction by dendritic cells in vivo. Front Immunol 9:350PubMedPubMedCentralCrossRefGoogle Scholar
  44. Heath V, Mason D, Ramirez F, Seddon B (1997) Homeostatic mechanisms in the control of autoimmunity. Semin Immunol 9:375–380PubMedCrossRefPubMedCentralGoogle Scholar
  45. Herzig Y, Nevo S, Bornstein C, Brezis MR, Ben-Hur S, Shkedy A, Eisenberg-Bord M, Levi B, Delacher M et al (2017) Transcriptional programs that control expression of the autoimmune regulator gene Aire. Nat Immunol 18:161–172PubMedCrossRefPubMedCentralGoogle Scholar
  46. Holländer GA (2007) Claudins provide a breath of fresh Aire. Nat Immunol 8:234–246PubMedCrossRefPubMedCentralGoogle Scholar
  47. Hu Z, Lancaster JN, Ehrlich L (2015) The contribution of chemokines and migration to the induction of central tolerance in the thymus. Front Immunol 6:398PubMedPubMedCentralCrossRefGoogle Scholar
  48. Hubert FX, Kinkel SA, Davey GM, Phipson B, Mueller SN, Liston A, Proietto AI, Cannon PZ, Forehan S, Smyth GK, Wu L, Goodnow CC, Carbone FR, Scott HS, Heath WR (2011) Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood 118:2462–2472PubMedCrossRefPubMedCentralGoogle Scholar
  49. Irla M, Hugues S, Gill J, Nitta T, Hikosaka Y, Williams IR, Hubert FX, Scott HS, Takahama Y, Holländer GA, Reith W (2008) Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity. Immunity 29:451–463CrossRefGoogle Scholar
  50. James KD, Jenkinson WE, Anderson G (2018) T-cell egress from the thymus: should I stay or should I go? J Leukoc Biol 104(2):275–284PubMedPubMedCentralCrossRefGoogle Scholar
  51. Kapranov P, Cheng J, Dike S, Nix DA, Duttagupta R, Willingham AT, Stadler PF, Hertel J, Hackermüller J et al (2007) RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 316(5830):1484–1488PubMedCrossRefPubMedCentralGoogle Scholar
  52. Keane P, Ceredig R, Seoighe C (2015) Promiscuous mRNA splicing under the control of AIRE in medullary thymic epithelial cells. Bioinformatics 31:986–990PubMedCrossRefPubMedCentralGoogle Scholar
  53. Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, Thomas K, Presser A, Bernstein BE et al (2009) Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A 106:11667–11672PubMedPubMedCentralCrossRefGoogle Scholar
  54. Khan IS, Tanigushi RT, Fasano KJ, Anderson MS, Jeker LT (2014) Canonical microRNAs in thymic epithelial cells promote central tolerance. Eur J Immunol 44:1313–1309PubMedPubMedCentralCrossRefGoogle Scholar
  55. Kirchner T, Hoppe F, Müller-Hermelink HK, Schalke B, Tzartos S (1987) Acetylcholine receptor epitopes on epithelial cells of thymoma in myasthenia gravis. Lancet 1:218PubMedCrossRefPubMedCentralGoogle Scholar
  56. Klein L (2015) Aire gets company for immune tolerance. Cell 163:794–795PubMedCrossRefPubMedCentralGoogle Scholar
  57. Klein L, Kyewski B (2000) Self-antigen presentation by thymic stromal cells: a subtle division of labor. Curr Opin Immunol 12:179–186PubMedCrossRefPubMedCentralGoogle Scholar
  58. Klein L, Hinterberger M, Wirnsberger G, Kyewski B (2009) Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol 9:833–844CrossRefGoogle Scholar
  59. Koble C, Kyewski B (2009) The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J Exp Med 206:1505–1513PubMedPubMedCentralCrossRefGoogle Scholar
  60. Kopp F, Mendell JT (2018) Functional classification and experimental dissection of long noncoding RNAs. Cell 172:393–407PubMedPubMedCentralCrossRefGoogle Scholar
  61. Kyewski B, Derbinski J (2004) Self-representation in the thymus: an extended view. Nat Rev Immunol 4:688–698PubMedCrossRefPubMedCentralGoogle Scholar
  62. Kyewski B, Kaplan HS (1982) Lymphoepithelial interactions in the mouse thymus: phenoptypic and kinetic studies on thymic nurse cells. J Immunol 128:2287–2294Google Scholar
  63. Kyewski B, Klein L (2006) A central role for central tolerance. Annu Rev Immunol 24:571–606PubMedCrossRefPubMedCentralGoogle Scholar
  64. Kyewski B, Derbinski J, Gotter J, Klein L (2002) Promiscuous gene expression and central T-cell tolerance: more than meets the eye. Trends Immunol 23:364–371PubMedCrossRefPubMedCentralGoogle Scholar
  65. Lei Y, Ripen AM, Ishimaru N, Ohigashi I, Nagasawa T, Jeker LT, Bösl MR, Holländer GA, Hayashi Y (2011) Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. J Exp Med 208:383–394PubMedPubMedCentralCrossRefGoogle Scholar
  66. Li J, Liu Z, Xiao S, Manley NR (2013) Transdifferentiation of parathyroid cells into cervical thymi promotes atypical T-cell development. Nat Commun 4:2959–2966PubMedPubMedCentralCrossRefGoogle Scholar
  67. Linhares-Lacerda L, Palu CC, Ribeiro-Alves M, Paredes BD, Morrot A, Garcia-Silva MR, Cayota A, Savino W (2015) Thymic epithelial cells from Trypanosoma cruzi acutely infected mice: role in thymic atrophy. Front Immunol 6:428PubMedPubMedCentralCrossRefGoogle Scholar
  68. Lodato S, Molyneaux BJ, Zuccaro E, Goff LA, Chen HH, Yuan W, Meleski A, Takahashi E, Mahony S, Rinn JL, Gifford DK, Arlotta P (2014) Gene co-regulation by Fezf2 selects neurotransmitter identity and connectivity of corticospinal neurons. Nat Neurosci 17:1046–1054PubMedPubMedCentralCrossRefGoogle Scholar
  69. Lopes N, Sergé A, Ferrier P, Irla M (2015) Thymic crosstalk coordinates medulla organization and T-cell tolerance induction. Front Immunol 6:365PubMedPubMedCentralCrossRefGoogle Scholar
  70. Lopes N, Charaix J, Cédile O, Sergé A, Irla M (2018) Lymphotoxin α fine-tunes T cell clonal deletion by regulating thymic entry of antigen-presenting cells. Nat Commun 9:1262PubMedPubMedCentralCrossRefGoogle Scholar
  71. Lynch HE, Goldberg GL, Chidgey A, Van den Brink MR, Boyd R, Sempowski GD (2009) Thymic involution and immune reconstitution. Trends Immunol 30:366–373PubMedPubMedCentralCrossRefGoogle Scholar
  72. Macedo C, Evangelista AF, Magalhães DA, Fornari TA, Linhares LL, Junta CM, Silva GL, Sakamoto-Hojo ET, Donadi EA, Savino W, Passos GA (2009) Evidence for a network transcriptional control of promiscuous gene expression in medullary thymic epithelial cells. Mol Immunol 46:3240–3244PubMedCrossRefPubMedCentralGoogle Scholar
  73. Macedo C, Evangelista AF, Marques MM, Octacílio-Silva S, Donadi EA, Sakamoto-Hojo ET, Passos GA (2013) Autoimmune regulator (Aire) controls the expression of microRNAs in medullary thymic epithelial cells. Immunobiology 218:554–560PubMedCrossRefPubMedCentralGoogle Scholar
  74. Macedo C, Oliveira EH, Almeida RS, Donate PB, Fornari TA, Pezzi N (2015) Aire-dependent peripheral tissue antigen mRNAs in mTEC cells feature network refractoriness to microRNA interaction. Immunobiology 220:93–102PubMedCrossRefPubMedCentralGoogle Scholar
  75. Magalhães DA, Silveira EL, Junta CM, Sandrin-Garcia P, Fachin AL, Donadi EA, Sakamoto-Hojo ET, Passos GA (2006) Promiscuous gene expression in the thymus: the root of central tolerance. Clin Dev Immunol 13:81–99PubMedPubMedCentralCrossRefGoogle Scholar
  76. Mendes-da-Cruz DA, Lemos JP, Passos GA, Savino W (2018) Abnormal T-cell development in the thymus of non-obese diabetic mice: possible relationship with the pathogenesis of Type 1 autoimmune diabetes. Front Endocrinol 9:381CrossRefGoogle Scholar
  77. Meredith M, Zemmour D, Mathis D, Benoist C (2015) Aire controls gene expression in the thymic epithelium with ordered stochasticity. Nat Immunol 16:942–949PubMedPubMedCentralCrossRefGoogle Scholar
  78. Meyer S, Woodward M, Hertel C, Vlaicu P, Haque Y, Kärner J, Macagno A, Onuoha SC, Fishman D et al (2016) AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies. Cell 166:582–595PubMedPubMedCentralCrossRefGoogle Scholar
  79. Mizuochi T, Kasai M, Kokuho T, Kakiuchi T, Hirokawa K (1992) Medullary but not cortical thymic epithelial cells present soluble antigens to helper T cells. J Exp Med 175:1601–1605PubMedCrossRefPubMedCentralGoogle Scholar
  80. Mouchess ML, Anderson M (2014) Central tolerance induction. Curr Top Microbiol Immunol 373:69–86PubMedPubMedCentralGoogle Scholar
  81. Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F, Shimizu N (1997) Positional cloning of the APECED gene. Nat Genet 17:393–398PubMedPubMedCentralCrossRefGoogle Scholar
  82. Nakagawa Y, Ohigashi I, Nitta T, Sakata M, Tanaka K, Murata S, Kanagawa O, Takahama Y (2012) Thymic nurse cells provide microenvironment for secondary T cell receptor α rearrangement in cortical thymocytes. Proc Natl Acad Sci U S A 109(50):20572–20577PubMedPubMedCentralCrossRefGoogle Scholar
  83. Oh J, Shin JS (2015) The role of dendritic cells in central tolerance. Immune Netw 15:111–120PubMedPubMedCentralCrossRefGoogle Scholar
  84. Oliveira EH, Macedo C, Collares CV, Freitas AC, Donate PB, Sakamoto-Hojo ET, Donadi EA, Passos GA (2016) Aire downregulation is associated with changes in the posttranscriptional control of peripheral tissue antigens in medullary thymic epithelial cells. Front Immunol 7:526PubMedPubMedCentralCrossRefGoogle Scholar
  85. Palmer S, Albergante L, Blackburn CC, Newman TJ (2018) Thymic involution and rising disease incidence with age. Proc Natl Acad Sci U S A 115:1883–1888PubMedPubMedCentralCrossRefGoogle Scholar
  86. Papadopoulou AS, Dooley J, Linterman MA, Pierson W, Ucar O, Kyewsky B, Hollander GA, Matthys P, Gray DH et al (2011) The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-α receptor. Nat Immunol 13:181–187PubMedPubMedCentralCrossRefGoogle Scholar
  87. Passos GA, Mendes-da-Cruz DA, Oliveira EH (2015) The thymic orchestration involving Aire, miRNAs and cell-cell interactions during the induction of central tolerance. Front Immunol 6:352PubMedPubMedCentralGoogle Scholar
  88. Passos GA, Speck-Hernandez CA, Assis AF, Mendes-da-Cruz DA (2018) Update on Aire and thymic negative selection. Immunology 153:10–20PubMedPubMedCentralCrossRefGoogle Scholar
  89. Pearson JA, Wong FS, Wen L (2016) The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes. J Autoimmun 66:76–88PubMedCrossRefPubMedCentralGoogle Scholar
  90. Perniola R (2018) Twenty years of AIRE. Front Immunol 9:98PubMedPubMedCentralCrossRefGoogle Scholar
  91. Pezzi N, Assis AF, Cotrim-Sousa L, Lopes GS, Mosella MS, Lima DS, Bombonato-Prado KF, Passos GA (2016) Aire knockdown in medullary thymic epithelial cells affects Aire protein, deregulates cell adhesion genes and decreases thymocyte interaction. Mol Immunol 77:157–173PubMedCrossRefPubMedCentralGoogle Scholar
  92. Pugliese A, Zeller M, Fernandez A Jr, Zalcberg LJ, Bartlett RJ, Ricordi C, Pietropaolo M, Eisenbarth GS, Bennett ST, Patel DD (1997) The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 15:293–297PubMedCrossRefPubMedCentralGoogle Scholar
  93. Rezzani R, Nardo L, Favero G, Peroni M, Rodella LF (2014) Thymus and aging: morphological, radiological, and functional overview. Age 36:313–351PubMedCrossRefPubMedCentralGoogle Scholar
  94. Sansom SN, Shikama-Dorn N, Zhanybekova S, Nusspaumer G, Macaulay IC, Deadman ME, Heger A, Ponting CP, Hollander GA (2014) Population and single-cell genomics reveal the Aire dependency relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia. Genome Res 24:1918–1931PubMedPubMedCentralCrossRefGoogle Scholar
  95. Savino W, Mendes-da-Cruz DA, Silva JS, Dardenne M, Cotta-de-Almeida V (2002) Intrathymic T-cell migration: a combinatorial interplay of extracellular matrix and chemokines? Trends Immunol 23:305–313CrossRefGoogle Scholar
  96. Savino W, Mendes-Da-Cruz DA, Smaniotto S, Silva-Monteiro E, Villa-Verde DM (2004) Molecular mechanisms governing thymocyte migration: combined role of chemokines and extracellular matrix. J Leukoc Biol 75:951–961PubMedCrossRefPubMedCentralGoogle Scholar
  97. Sawanobori Y, Ueta H, Dijkstra CD, Park CG, Satou M, Kitazawa Y, Matsuno K (2014) Three distinct subsets of thymic epithelial cells in rats and mice defined by novel antibodies. PLoS One 9(10):e109995PubMedPubMedCentralCrossRefGoogle Scholar
  98. Sospedra M, Ferrer-Francesch X, Domínguez O, Juan M, Foz-Sala M, Pujol-Borrell R (1998) Transcription of a broad range of self-antigens in human thymus suggests a role for central mechanisms in tolerance toward peripheral antigens. J Immunol 161:5918–5929PubMedPubMedCentralGoogle Scholar
  99. Sousa Cardoso R, Magalhães DA, Baião AM, Junta CM, Macedo C, Marques MM, Sakamoto-Hojo ET, Donadi EA, Passos GA (2006) Onset of promiscuous gene expression in murine fetal thymus organ culture. Immunology 119:369–375PubMedPubMedCentralCrossRefGoogle Scholar
  100. Speck-Hernandez CA, Assis AF, Felicio RF, Cotrim-Sousa L, Pezzi N, Lopes GS, Bombonato-Prado KF, Giuliatti S, Passos GA (2018) Aire disruption influences the medullary thymic epithelial cell transcriptome and interaction with thymocytes. Front Immunol 9:964PubMedPubMedCentralCrossRefGoogle Scholar
  101. St-Pierre C, Brochu S, Vanegas JR, Dumont-Lagacé M, Lemieux S, Perreault C (2013) Transcriptome sequencing of neonatal thymic epithelial cells. Sci Rep 3:1860PubMedPubMedCentralCrossRefGoogle Scholar
  102. St-Pierre C, Trofimov A, Brochu S, Lemieux S, Perreault C (2015) Differential features of AIRE-induced and AIRE-independent promiscuous gene expression in thymic epithelial cells. J Immunol 195:498–506PubMedCrossRefPubMedCentralGoogle Scholar
  103. Takaba H, Takayanagi H (2017) The mechanisms of T cell selection in the thymus. Trends Immunol 38:805–816PubMedCrossRefPubMedCentralGoogle Scholar
  104. Takaba H, Morishita Y, Tomofuji Y, Danks L, Nitta T, Komatsu N, Kodama T, Takayanagi H (2015) Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163:975–987CrossRefPubMedPubMedCentralGoogle Scholar
  105. Takahama Y (2006) Journey through the thymus: stromal guides for T-cell development and selection. Nat Rev Immunol 6:127–135CrossRefGoogle Scholar
  106. Taub DD, Longo DL (2005) Insights into thymic aging and regeneration. Immunol Rev 205:72–93PubMedCrossRefPubMedCentralGoogle Scholar
  107. Terszowski G, Müller SM, Bleul CC, Blum C, Schirmbeck R, Reimann J, Pasquier LD, Amagai T, Boehm T et al (2006) Evidence for a functional second thymus in mice. Science 312:284–287PubMedCrossRefPubMedCentralGoogle Scholar
  108. Tykocinski LO, Sinemus A, Kyewski B (2008) The thymus medulla slowly yields its secrets. Ann N Y Acad Sci 1143:105–122PubMedCrossRefPubMedCentralGoogle Scholar
  109. Ucar O, Rattay K (2015) Promiscuous gene expression in the thymus: a matter of epigenetics, miRNA, and more? Front Immunol 6:93PubMedPubMedCentralCrossRefGoogle Scholar
  110. Ucar O, Tykocinski LO, Dooley J, Liston A, Kyewski B (2013) An evolutionarily conserved mutual interdependence between Aire and microRNAs in promiscuous gene expression. Eur J Immunol 43:1769–1778PubMedPubMedCentralCrossRefGoogle Scholar
  111. Vafiadis P, Bennett ST, Colle E, Grabs R, Goodyer CG, Polychronakos C (1996) Imprinted and genotype-specific expression of genes at the IDDM2 locus in pancreas and leucocytes. J Autoimmun 9:397–403PubMedCrossRefPubMedCentralGoogle Scholar
  112. Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG, Wickramasinghe S, Colle E, Polychronakos C (1997) Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 15:289–292PubMedCrossRefPubMedCentralGoogle Scholar
  113. Villaseñor J, Besse W, Benoist C, Mathis D (2008) Ectopic expression of peripheral-tissue antigens in the thymic epithelium: probabilistic, monoallelic, misinitiated. Proc Natl Acad Sci U S A 105:15854–15859PubMedPubMedCentralCrossRefGoogle Scholar
  114. Wang KC, Chang HY (2011) Molecular mechanisms of long noncoding RNAs. Mol Cell 43:904–914PubMedPubMedCentralCrossRefGoogle Scholar
  115. Werdelin O, Cordes U, Jensen T (1998) Aberrant expression of tissue-specific proteins in the thymus: a hypothesis for the development of central tolerance. Scand J Immunol 47:95–100PubMedCrossRefPubMedCentralGoogle Scholar
  116. Wilusz JE, Sunwoo H, Spector DL (2009) Long noncoding RNAs: functional surprises from the RNA world. Genes Dev 1(23):1494–1504CrossRefGoogle Scholar
  117. Xu M, Zhang X, Hong R, Su D-M, Wang L (2017) MicroRNAs regulate thymic epithelium in age-related thymic involution via down- or upregulation of transcription factors. J Immunol Res 2017:2528957PubMedPubMedCentralGoogle Scholar
  118. Yano M, Kuroda N, Han H, Meguro-Horike M, Nishikawa Y, Kiyonari H, Maemura K, Yanagawa Y, Obata K, Takahashi S, Ikawa T, Satoh R, Kawamoto H, Mouri Y, Matsumoto M (2008) Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance. J Exp Med 205:2827–2838PubMedPubMedCentralCrossRefGoogle Scholar
  119. Zuklys S, Mayer CE, Zhanybekova S, Stefanski HE, Nusspaumer G, Gill J, Barthlott T, Chappaz S, Nitta T et al (2012) MicroRNAs control the maintenance of thymic epithelia and their competence for T lineage commitment and thymocyte selection. J Immunol 189:3894–3904PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Geraldo A. Passos
    • 1
    • 2
    Email author
  • Adriana B. Genari
    • 2
  • Amanda F. Assis
    • 2
  • Ana C. Monteleone-Cassiano
    • 2
  • Eduardo A. Donadi
    • 3
  • Ernna H. Oliveira
    • 2
  • Max J. Duarte
    • 2
  • Mayara V. Machado
    • 2
  • Pedro P. Tanaka
    • 2
  • Romário Mascarenhas
    • 2
  1. 1.Laboratory of Genetics and Molecular Biology, Department of Basic and Oral Biology, School of Dentistry of Ribeirão PretoUniversity of São PauloRibeirão PretoBrazil
  2. 2.Molecular Immunogenetics Group, Department of Genetics, Ribeirão Preto Medical SchoolUniversity of São PauloRibeirão PretoBrazil
  3. 3.Department of Clinical Medicine, Ribeirão Preto Medical SchoolUniversity of São PauloRibeirão PretoBrazil

Personalised recommendations