The Ins and Outs of Thymic Epithelial Cell Differentiation and Function

  • Minoru Matsumoto
  • Pedro M. Rodrigues
  • Laura Sousa
  • Koichi Tsuneyama
  • Mitsuru MatsumotoEmail author
  • Nuno L. AlvesEmail author


The thymus is the organ dedicated to the generation of T cells, which are key effector cells in immune clearance of pathogens and tumours. However, T cells can also react to our own tissues or turn into cancer cells, such as in the case of autoimmunity and leukaemia, respectively. Therefore, the development and selection of T cells is a tightly regulated process that proceeds within inductive thymic microenvironments formed by cortical (c) and medullary (m) thymic epithelial cells (TECs). Herein, we critically summarize our current knowledge on the molecular principles underlying the development and diversification of TEC compartments and highlight their specialized roles in specific stages of T cell development. Knowledge in this area is of fundamental and clinical relevance to understand how the immune system reaches the equilibrium between immunity and tolerance induction.



The European Research Council (ERC) under the EU’s Horizon 2020 research and innovation program (grant agreement No 637843—TEC_Pro)—starting grant attributed to N.L.A—supports the studies from the laboratory of Nuno L. Alves. The studies from the laboratory of Mitsuru Matsumoto are supported by JSPS KAKENHI Grant Numbers JP16H06496 and JP16H05342, and by the Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology. We apologize for not referring to all of the primary literature owing to the space limitations.


  1. Abramson J, Anderson G (2017) Thymic epithelial cells. Annu Rev Immunol 35:85–118PubMedCrossRefPubMedCentralGoogle Scholar
  2. Abramson J, Giraud M, Benoist C, Mathis D (2010) Aire’s partners in the molecular control of immunological tolerance. Cell 140(1):123–135CrossRefPubMedPubMedCentralGoogle Scholar
  3. Akiyama T, Maeda S, Yamane S, Ogino K, Kasai M, Kajiura F, Matsumoto M, Inoue J (2005) Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 308(5719):248–251PubMedCrossRefGoogle Scholar
  4. Akiyama T, Shimo Y, Yanai H, Qin J, Ohshima D, Maruyama Y, Asaumi Y, Kitazawa J, Takayanagi H, Penninger JM, Matsumoto M, Nitta T, Takahama Y, Inoue J (2008) The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29(3):423–437PubMedPubMedCentralCrossRefGoogle Scholar
  5. Alves NL, Huntington ND, Rodewald HR, Di Santo JP (2009a) Thymic epithelial cells: the multi-tasking framework of the T cell “cradle”. Trends Immunol 30(10):468–474PubMedCrossRefGoogle Scholar
  6. Alves NL, Richard-Le Goff O, Huntington ND, Sousa AP, Ribeiro VS, Bordack A, Vives FL, Peduto L, Chidgey A, Cumano A, Boyd R, Eberl G, Di Santo JP (2009b) Characterization of the thymic IL-7 niche in vivo. Proc Natl Acad Sci U S A 106(5):1512–1517PubMedPubMedCentralCrossRefGoogle Scholar
  7. Alves NL, Huntington ND, Mention JJ, Richard-Le Goff O, Di Santo JP (2010) Cutting edge: a thymocyte-thymic epithelial cell cross-talk dynamically regulates intrathymic IL-7 expression in vivo. J Immunol 184(11):5949–5953PubMedCrossRefGoogle Scholar
  8. Alves NL, Takahama Y, Ohigashi I, Ribeiro AR, Baik S, Anderson G, Jenkinson WE (2014) Serial progression of cortical and medullary thymic epithelial microenvironments. Eur J Immunol 44(1):16–22PubMedCrossRefGoogle Scholar
  9. Anderson G, Takahama Y (2012) Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol 33(6):256–263PubMedCrossRefGoogle Scholar
  10. Anderson G, Jenkinson EJ, Moore NC, Owen JJ (1993) MHC class II-positive epithelium and mesenchyme cells are both required for T-cell development in the thymus. Nature 362(6415):70–73PubMedCrossRefGoogle Scholar
  11. Anderson G, Anderson KL, Tchilian EZ, Owen JJ, Jenkinson EJ (1997) Fibroblast dependency during early thymocyte development maps to the CD25+ CD44+ stage and involves interactions with fibroblast matrix molecules. Eur J Immunol 27(5):1200–1206PubMedCrossRefGoogle Scholar
  12. 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(5597):1395–1401CrossRefPubMedPubMedCentralGoogle Scholar
  13. Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D (2005) The cellular mechanism of aire control of T cell tolerance. Immunity 23(2):227–239PubMedCrossRefGoogle Scholar
  14. Anderson G, Lane PJ, Jenkinson EJ (2007) Generating intrathymic microenvironments to establish T-cell tolerance. Nat Rev Immunol 7(12):954–963PubMedCrossRefPubMedCentralGoogle Scholar
  15. 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(4):351–358PubMedCrossRefPubMedCentralGoogle Scholar
  16. Aw D, Silva AB, Maddick M, von Zglinicki T, Palmer DB (2008) Architectural changes in the thymus of aging mice. Aging Cell 7(2):158–167PubMedCrossRefGoogle Scholar
  17. Aw D, Taylor-Brown F, Cooper K, Palmer DB (2009) Phenotypical and morphological changes in the thymic microenvironment from ageing mice. Biogerontology 10(3):311–322PubMedCrossRefGoogle Scholar
  18. Baik S, Jenkinson EJ, Lane PJ, Anderson G, Jenkinson WE (2013) Generation of both cortical and aire(+) medullary thymic epithelial compartments from CD205(+) progenitors. Eur J Immunol 43(3):589–594PubMedPubMedCentralCrossRefGoogle Scholar
  19. Baik S, Sekai M, Hamazaki Y, Jenkinson WE, Anderson G (2016) Relb acts downstream of medullary thymic epithelial stem cells and is essential for the emergence of RANK(+) medullary epithelial progenitors. Eur J Immunol 46(4):857–862PubMedPubMedCentralCrossRefGoogle Scholar
  20. Balciunaite G, Keller MP, Balciunaite E, Piali L, Zuklys S, Mathieu YD, Gill J, Boyd R, Sussman DJ, Hollander GA (2002) Wnt glycoproteins regulate the expression of FoxN1, the gene defective in nude mice. Nat Immunol 3(11):1102–1108PubMedPubMedCentralCrossRefGoogle Scholar
  21. Banwell CM, Partington KM, Jenkinson EJ, Anderson G (2000) Studies on the role of IL-7 presentation by mesenchymal fibroblasts during early thymocyte development. Eur J Immunol 30(8):2125–2129PubMedCrossRefGoogle Scholar
  22. Barr IG, Khalid BA, Pearce P, Toh BH, Bartlett PF, Scollay RG, Funder JW (1982) Dihydrotestosterone and estradiol deplete corticosensitive thymocytes lacking in receptors for these hormones. J Immunol 128(6):2825–2828PubMedGoogle Scholar
  23. Bennett AR, Farley A, Blair NF, Gordon J, Sharp L, Blackburn CC (2002) Identification and characterization of thymic epithelial progenitor cells. Immunity 16(6):803–814PubMedCrossRefGoogle Scholar
  24. Blackburn CC, Manley NR (2004) Developing a new paradigm for thymus organogenesis. Nat Rev Immunol 4(4):278–289PubMedPubMedCentralCrossRefGoogle Scholar
  25. Blackburn CC, Augustine CL, Li R, Harvey RP, Malin MA, Boyd RL, Miller JF, Morahan G (1996) The nu gene acts cell-autonomously and is required for differentiation of thymic epithelial progenitors. Proc Natl Acad Sci U S A 93(12):5742–5746PubMedPubMedCentralCrossRefGoogle Scholar
  26. Bleul CC, Boehm T (2000) Chemokines define distinct microenvironments in the developing thymus. Eur J Immunol 30(12):3371–3379PubMedCrossRefGoogle Scholar
  27. Bleul CC, Corbeaux T, Reuter A, Fisch P, Monting JS, Boehm T (2006) Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 441(7096):992–996PubMedPubMedCentralCrossRefGoogle Scholar
  28. Boehm T, Scheu S, Pfeffer K, Bleul CC (2003) Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LT{beta}R. J Exp Med 198(5):757–769PubMedPubMedCentralCrossRefGoogle Scholar
  29. Boyd RL, Tucek CL, Godfrey DI, Izon DJ, Wilson TJ, Davidson NJ, Bean AG, Ladyman HM, Ritter MA, Hugo P (1993) The thymic microenvironment. Immunol Today 14(9):445–459PubMedCrossRefGoogle Scholar
  30. Bredenkamp N, Nowell CS, Blackburn CC (2014a) Regeneration of the aged thymus by a single transcription factor. Development 141(8):1627–1637PubMedPubMedCentralCrossRefGoogle Scholar
  31. Bredenkamp N, Ulyanchenko S, O’Neill KE, Manley NR, Vaidya HJ, Blackburn CC (2014b) An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts. Nat Cell Biol 16(9):902–908PubMedPubMedCentralCrossRefGoogle Scholar
  32. Buono M, Facchini R, Matsuoka S, Thongjuea S, Waithe D, Luis TC, Giustacchini A, Besmer P, Mead AJ, Jacobsen SE, Nerlov C (2016) A dynamic niche provides Kit ligand in a stage-specific manner to the earliest thymocyte progenitors. Nat Cell Biol 18(2):157–167PubMedPubMedCentralCrossRefGoogle Scholar
  33. Calderon L, Boehm T (2011) Three chemokine receptors cooperatively regulate homing of hematopoietic progenitors to the embryonic mouse thymus. Proc Natl Acad Sci U S A 108(18):7517–7522PubMedPubMedCentralCrossRefGoogle Scholar
  34. Chen L, Xiao S, Manley NR (2009) Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner. Blood 113(3):567–574PubMedPubMedCentralCrossRefGoogle Scholar
  35. Chinn IK, Blackburn CC, Manley NR, Sempowski GD (2012) Changes in primary lymphoid organs with aging. Semin Immunol 24(5):309–320PubMedPubMedCentralCrossRefGoogle Scholar
  36. Chuprin A, Avin A, Goldfarb Y, Herzig Y, Levi B, Jacob A, Sela A, Katz S, Grossman M, Guyon C, Rathaus M, Cohen HY, Sagi I, Giraud M, McBurney MW, Husebye ES, Abramson J (2015) The deacetylase Sirt1 is an essential regulator of aire-mediated induction of central immunological tolerance. Nat Immunol 16(7):737–745PubMedCrossRefGoogle Scholar
  37. Ciofani M, Zuniga-Pflucker JC (2007) The thymus as an inductive site for T lymphopoiesis. Annu Rev Cell Dev Biol 23:463–493PubMedCrossRefGoogle Scholar
  38. Consortium TF-GA (1997) An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet 17(4):399–403CrossRefGoogle Scholar
  39. Corbeaux T, Hess I, Swann JB, Kanzler B, Haas-Assenbaum A, Boehm T (2010) Thymopoiesis in mice depends on a Foxn1-positive thymic epithelial cell lineage. Proc Natl Acad Sci U S A 107(38):16613–16618PubMedPubMedCentralCrossRefGoogle Scholar
  40. De Togni P, Goellner J, Ruddle NH, Streeter PR, Fick A, Mariathasan S, Smith SC, Carlson R, Shornick LP, Strauss-Schoenberger J et al (1994) Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264(5159):703–707PubMedCrossRefGoogle Scholar
  41. Derbinski J, Schulte A, Kyewski B, Klein L (2001) Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2(11):1032–1039CrossRefPubMedPubMedCentralGoogle Scholar
  42. Edelson BT, Kc W, Juang R, Kohyama M, Benoit LA, Klekotka PA, Moon C, Albring JC, Ise W, Michael DG, Bhattacharya D, Stappenbeck TS, Holtzman MJ, Sung SS, Murphy TL, Hildner K, Murphy KM (2010) Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8alpha+ conventional dendritic cells. J Exp Med 207(4):823–836PubMedPubMedCentralCrossRefGoogle Scholar
  43. Esashi E, Sekiguchi T, Ito H, Koyasu S, Miyajima A (2003) Cutting edge: a possible role for CD4+ thymic macrophages as professional scavengers of apoptotic thymocytes. J Immunol 171(6):2773–2777PubMedCrossRefGoogle Scholar
  44. van Ewijk W, Shores EW, Singer A (1994) Crosstalk in the mouse thymus. Immunol Today 15(5):214–217CrossRefGoogle Scholar
  45. van Ewijk W, Hollander G, Terhorst C, Wang B (2000) Stepwise development of thymic microenvironments in vivo is regulated by thymocyte subsets. Development 127(8):1583–1591Google Scholar
  46. Farr AG, Anderson SK (1985) Epithelial heterogeneity in the murine thymus: fucose-specific lectins bind medullary epithelial cells. J Immunol 134(5):2971–2977Google Scholar
  47. Fiorini E, Ferrero I, Merck E, Favre S, Pierres M, Luther SA, MacDonald HR (2008) Cutting edge: thymic crosstalk regulates delta-like 4 expression on cortical epithelial cells. J Immunol 181(12):8199–8203PubMedCrossRefGoogle Scholar
  48. Garfin PM, Min D, Bryson JL, Serwold T, Edris B, Blackburn CC, Richie ER, Weinberg KI, Manley NR, Sage J, Viatour P (2013) Inactivation of the RB family prevents thymus involution and promotes thymic function by direct control of Foxn1 expression. J Exp Med 210(6):1087–1097PubMedPubMedCentralCrossRefGoogle Scholar
  49. Gill J, Malin M, Hollander GA, Boyd R (2002) Generation of a complete thymic microenvironment by MTS24(+) thymic epithelial cells. Nat Immunol 3(7):635–642PubMedCrossRefGoogle Scholar
  50. Gillard GO, Dooley J, Erickson M, Peltonen L, Farr AG (2007) Aire-dependent alterations in medullary thymic epithelium indicate a role for aire in thymic epithelial differentiation. J Immunol 178(5):3007–3015PubMedCrossRefGoogle Scholar
  51. Godfrey DI, Izon DJ, Tucek CL, Wilson TJ, Boyd RL (1990) The phenotypic heterogeneity of mouse thymic stromal cells. Immunology 70(1):66–74PubMedPubMedCentralGoogle Scholar
  52. Gommeaux J, Gregoire C, Nguessan P, Richelme M, Malissen M, Guerder S, Malissen B, Carrier A (2009) Thymus-specific serine protease regulates positive selection of a subset of CD4+ thymocytes. Eur J Immunol 39(4):956–964PubMedCrossRefGoogle Scholar
  53. Gordon J, Manley NR (2011) Mechanisms of thymus organogenesis and morphogenesis. Development 138(18):3865–3878PubMedPubMedCentralCrossRefGoogle Scholar
  54. Gordon J, Bennett AR, Blackburn CC, Manley NR (2001) Gcm2 and Foxn1 mark early parathyroid- and thymus-specific domains in the developing third pharyngeal pouch. Mech Dev 103(1-2):141–143PubMedPubMedCentralCrossRefGoogle Scholar
  55. Gossens K, Naus S, Corbel SY, Lin S, Rossi FM, Kast J, Ziltener HJ (2009) Thymic progenitor homing and lymphocyte homeostasis are linked via S1P-controlled expression of thymic P-selectin/CCL25. J Exp Med 206(4):761–778PubMedPubMedCentralCrossRefGoogle Scholar
  56. Gray DH, Seach N, Ueno T, Milton MK, Liston A, Lew AM, Goodnow CC, Boyd RL (2006) Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 108(12):3777–3785PubMedPubMedCentralCrossRefGoogle Scholar
  57. Greenstein BD, Fitzpatrick FT, Kendall MD, Wheeler MJ (1987) Regeneration of the thymus in old male rats treated with a stable analogue of LHRH. J Endocrinol 112(3):345–350PubMedCrossRefGoogle Scholar
  58. Grossman CJ (1985) Interactions between the gonadal steroids and the immune system. Science 227(4684):257–261PubMedCrossRefGoogle Scholar
  59. Gui J, Zhu X, Dohkan J, Cheng L, Barnes PF, Su DM (2007) The aged thymus shows normal recruitment of lymphohematopoietic progenitors but has defects in thymic epithelial cells. Int Immunol 19(10):1201–1211PubMedCrossRefGoogle Scholar
  60. Hadden JW (1998) Thymic endocrinology. Ann N Y Acad Sci 840:352–358PubMedCrossRefGoogle Scholar
  61. Hale JS, Boursalian TE, Turk GL, Fink PJ (2006) Thymic output in aged mice. Proc Natl Acad Sci U S A 103(22):8447–8452PubMedPubMedCentralCrossRefGoogle Scholar
  62. Haljasorg U, Dooley J, Laan M, Kisand K, Bichele R, Liston A, Peterson P (2017) Irf4 expression in thymic epithelium is critical for thymic regulatory T cell homeostasis. J Immunol 198(5):1952–1960CrossRefGoogle Scholar
  63. Hamazaki Y, Fujita H, Kobayashi T, Choi Y, Scott HS, Matsumoto M, Minato N (2007) Medullary thymic epithelial cells expressing aire represent a unique lineage derived from cells expressing claudin. Nat Immunol 8(3):304–311CrossRefGoogle Scholar
  64. Hamazaki Y, Sekai M, Minato N (2016) Medullary thymic epithelial stem cells: role in thymic epithelial cell maintenance and thymic involution. Immunol Rev 271(1):38–55PubMedCrossRefGoogle Scholar
  65. Hanahan D (1998) Peripheral-antigen-expressing cells in thymic medulla: factors in self-tolerance and autoimmunity. Curr Opin Immunol 10(6):656–662PubMedCrossRefPubMedCentralGoogle Scholar
  66. Heng TS, Goldberg GL, Gray DH, Sutherland JS, Chidgey AP, Boyd RL (2005) Effects of castration on thymocyte development in two different models of thymic involution. J Immunol 175(5):2982–2993PubMedCrossRefGoogle Scholar
  67. Hince M, Sakkal S, Vlahos K, Dudakov J, Boyd R, Chidgey A (2008) The role of sex steroids and gonadectomy in the control of thymic involution. Cell Immunol 252(1-2):122–138PubMedCrossRefGoogle Scholar
  68. Hofmann J, Mair F, Greter M, Schmidt-Supprian M, Becher B (2011) NIK signaling in dendritic cells but not in T cells is required for the development of effector T cells and cell-mediated immune responses. J Exp Med 208(9):1917–1929PubMedPubMedCentralCrossRefGoogle Scholar
  69. 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(9):2462–2472PubMedCrossRefPubMedCentralGoogle Scholar
  70. Jain R, Sheridan JM, Policheni A, Heinlein M, Gandolfo LC, Dewson G, Smyth GK, Sansom SN, Fu NY, Visvader JE, Hollander GA, Strasser A, Gray DHD (2017) A critical epithelial survival axis regulated by MCL-1 maintains thymic function in mice. Blood 130(23):2504–2515PubMedPubMedCentralCrossRefGoogle Scholar
  71. Jenkinson WE, Rossi SW, Parnell SM, Jenkinson EJ, Anderson G (2007) PDGFRalpha-expressing mesenchyme regulates thymus growth and the availability of intrathymic niches. Blood 109(3):954–960PubMedPubMedCentralCrossRefGoogle Scholar
  72. Kajiura F, Sun S, Nomura T, Izumi K, Ueno T, Bando Y, Kuroda N, Han H, Li Y, Matsushima A, Takahama Y, Sakaguchi S, Mitani T, Matsumoto M (2004) NF-kappaB-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner. J Immunol 172(4):2067–2075PubMedPubMedCentralCrossRefGoogle Scholar
  73. Kawano H, Nishijima H, Morimoto J, Hirota F, Morita R, Mouri Y, Nishioka Y, Matsumoto M (2015) Aire expression is inherent to most medullary thymic epithelial cells during their differentiation program. J Immunol 195(11):5149–5158PubMedCrossRefGoogle Scholar
  74. Ki S, Park D, Selden HJ, Seita J, Chung H, Kim J, Iyer VR, Ehrlich LIR (2014) Global transcriptional profiling reveals distinct functions of thymic stromal subsets and age-related changes during thymic involution. Cell Rep 9(1):402–415PubMedPubMedCentralCrossRefGoogle Scholar
  75. Kinoshita D, Hirota F, Kaisho T, Kasai M, Izumi K, Bando Y, Mouri Y, Matsushima A, Niki S, Han H, Oshikawa K, Kuroda N, Maegawa M, Irahara M, Takeda K, Akira S, Matsumoto M (2006) Essential role of IkappaB kinase alpha in thymic organogenesis required for the establishment of self-tolerance. J Immunol 176(7):3995–4002PubMedCrossRefGoogle Scholar
  76. 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(12):833–844CrossRefGoogle Scholar
  77. Klein L, Kyewski B, Allen PM, Hogquist KA (2014) Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nat Rev Immunol 14(6):377–391PubMedPubMedCentralCrossRefGoogle Scholar
  78. Klug DB, Carter C, Crouch E, Roop D, Conti CJ, Richie ER (1998) Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc Natl Acad Sci U S A 95(20):11822–11827PubMedPubMedCentralCrossRefGoogle Scholar
  79. Klug DB, Carter C, Gimenez-Conti IB, Richie ER (2002) Cutting edge: thymocyte-independent and thymocyte-dependent phases of epithelial patterning in the fetal thymus. J Immunol 169(6):2842–2845PubMedCrossRefGoogle Scholar
  80. Koch U, Fiorini E, Benedito R, Besseyrias V, Schuster-Gossler K, Pierres M, Manley NR, Duarte A, Macdonald HR, Radtke F (2008) Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. J Exp Med 205(11):2515–2523PubMedPubMedCentralCrossRefGoogle Scholar
  81. Koh AS, Miller EL, Buenrostro JD, Moskowitz DM, Wang J, Greenleaf WJ, Chang HY, Crabtree GR (2018) Rapid chromatin repression by aire provides precise control of immune tolerance. Nat Immunol 19(2):162–172PubMedPubMedCentralCrossRefGoogle Scholar
  82. Krueger A, Willenzon S, Lyszkiewicz M, Kremmer E, Forster R (2010) CC chemokine receptor 7 and 9 double-deficient hematopoietic progenitors are severely impaired in seeding the adult thymus. Blood 115(10):1906–1912PubMedPubMedCentralCrossRefGoogle Scholar
  83. Kuroda N, Mitani T, Takeda N, Ishimaru N, Arakaki R, Hayashi Y, Bando Y, Izumi K, Takahashi T, Nomura T, Sakaguchi S, Ueno T, Takahama Y, Uchida D, Sun S, Kajiura F, Mouri Y, Han H, Matsushima A, Yamada G, Matsumoto M (2005) Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of aire-deficient mice. J Immunol 174(4):1862–1870PubMedCrossRefGoogle Scholar
  84. Kyewski B, Klein L (2006) A central role for central tolerance. Annu Rev Immunol 24:571–606PubMedCrossRefPubMedCentralGoogle Scholar
  85. Lee H, Kim H, Chung Y, Kim J, Yang H (2013) Thymocyte differentiation is regulated by a change in estradiol levels during the estrous cycle in mouse. Dev Reprod 17(4):441–449PubMedPubMedCentralCrossRefGoogle Scholar
  86. Liang Z, Zhang L, Su H, Luan R, Na N, Sun L, Zhao Y, Zhang X, Zhang Q, Li J, Zhang L, Zhao Y (2018) MTOR signaling is essential for the development of thymic epithelial cells and the induction of central immune tolerance. Autophagy 14(3):505–517PubMedPubMedCentralCrossRefGoogle Scholar
  87. Linton PJ, Dorshkind K (2004) Age-related changes in lymphocyte development and function. Nat Immunol 5(2):133–139PubMedCrossRefGoogle Scholar
  88. Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC (2003) Aire regulates negative selection of organ-specific T cells. Nat Immunol 4(4):350–354PubMedCrossRefGoogle Scholar
  89. Liu C, Saito F, Liu Z, Lei Y, Uehara S, Love P, Lipp M, Kondo S, Manley N, Takahama Y (2006) Coordination between CCR7- and CCR9-mediated chemokine signals in prevascular fetal thymus colonization. Blood 108(8):2531–2539PubMedCrossRefGoogle Scholar
  90. Liu Z, Yu S, Manley NR (2007) Gcm2 is required for the differentiation and survival of parathyroid precursor cells in the parathyroid/thymus primordia. Dev Biol 305(1):333–346PubMedPubMedCentralCrossRefGoogle Scholar
  91. Lomada D, Jain M, Bolner M, Reeh KA, Kang R, Reddy MC, DiGiovanni J, Richie ER (2016) Stat3 signaling promotes survival and maintenance of medullary thymic epithelial cells. PLoS Genet 12(1):e1005777PubMedPubMedCentralCrossRefGoogle Scholar
  92. Love PE, Bhandoola A (2011) Signal integration and crosstalk during thymocyte migration and emigration. Nat Rev Immunol 11(7):469–477PubMedPubMedCentralCrossRefGoogle Scholar
  93. Malchow S, Leventhal DS, Nishi S, Fischer BI, Shen L, Paner GP, Amit AS, Kang C, Geddes JE, Allison JP, Socci ND, Savage PA (2013) Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339(6124):1219–1224PubMedPubMedCentralCrossRefGoogle Scholar
  94. Manley NR (2000) Thymus organogenesis and molecular mechanisms of thymic epithelial cell differentiation. Semin Immunol 12(5):421–428PubMedCrossRefGoogle Scholar
  95. Matsumoto M (2007) Transcriptional regulation in thymic epithelial cells for the establishment of self tolerance. Arch Immunol Ther Exp (Warsz) 55:27–34CrossRefGoogle Scholar
  96. Matsumoto M, Fu YX, Molina H, Chaplin DD (1997) Lymphotoxin-alpha-deficient and TNF receptor-I-deficient mice define developmental and functional characteristics of germinal centers. Immunol Rev 156:137–144PubMedCrossRefGoogle Scholar
  97. Matsumoto M, Iwamasa K, Rennert PD, Yamada T, Suzuki R, Matsushima A, Okabe M, Fujita S, Yokoyama M (1999) Involvement of distinct cellular compartments in the abnormal lymphoid organogenesis in lymphotoxin-alpha-deficient mice and alymphoplasia (aly) mice defined by the chimeric analysis. J Immunol 163(3):1584–1591PubMedGoogle Scholar
  98. Matsumoto M, Nishikawa Y, Nishijima H, Morimoto J, Matsumoto M, Mouri Y (2013) Which model better fits the role of aire in the establishment of self-tolerance: the transcription model or the maturation model? Front Immunol 4:210PubMedPubMedCentralCrossRefGoogle Scholar
  99. Matsushima A, Kaisho T, Rennert PD, Nakano H, Kurosawa K, Uchida D, Takeda K, Akira S, Matsumoto M (2001) Essential role of nuclear factor (NF)-kappaB-inducing kinase and inhibitor of kappaB (IkappaB) kinase alpha in NF-kappaB activation through lymphotoxin beta receptor, but not through tumor necrosis factor receptor I. J Exp Med 193(5):631–636PubMedPubMedCentralCrossRefGoogle Scholar
  100. Mayer CE, Zuklys S, Zhanybekova S, Ohigashi I, Teh HY, Sansom SN, Shikama-Dorn N, Hafen K, Macaulay IC, Deadman ME, Ponting CP, Takahama Y, Hollander GA (2016) Dynamic spatio-temporal contribution of single beta5t+ cortical epithelial precursors to the thymus medulla. Eur J Immunol 46(4):846–856PubMedPubMedCentralCrossRefGoogle Scholar
  101. Meireles C, Ribeiro AR, Pinto RD, Leitao C, Rodrigues PM, Alves NL (2017) Thymic crosstalk restrains the pool of cortical thymic epithelial cells with progenitor properties. Eur J Immunol 47(6):958–969PubMedCrossRefGoogle Scholar
  102. Metzger TC, Khan IS, Gardner JM, Mouchess ML, Johannes KP, Krawisz AK, Skrzypczynska KM, Anderson MS (2013) Lineage tracing and cell ablation identify a post-aire-expressing thymic epithelial cell population. Cell Rep 5(1):166–179CrossRefPubMedPubMedCentralGoogle Scholar
  103. Miller JFAP (1961) Imunological function of the thymus. Lancet 2(7205):748–749CrossRefGoogle Scholar
  104. Miller JF (2006) Vestigial no more. Nat Immunol 7(1):3–5PubMedCrossRefGoogle Scholar
  105. Moore TA, von Freeden-Jeffry U, Murray R, Zlotnik A (1996) Inhibition of gamma delta T cell development and early thymocyte maturation in IL-7 -/- mice. J Immunol 157(6):2366–2373PubMedGoogle Scholar
  106. Morrissey PJ, Charrier K, Alpert A, Bressler L (1988) In vivo administration of IL-1 induces thymic hypoplasia and increased levels of serum corticosterone. J Immunol 141(5):1456–1463PubMedGoogle Scholar
  107. Mouri Y, Yano M, Shinzawa M, Shimo Y, Hirota F, Nishikawa Y, Nii T, Kiyonari H, Abe T, Uehara H, Izumi K, Tamada K, Chen L, Penninger JM, Inoue J, Akiyama T, Matsumoto M (2011) Lymphotoxin signal promotes thymic organogenesis by eliciting RANK expression in the embryonic thymic stroma. J Immunol 186(9):5047–5057CrossRefGoogle Scholar
  108. Mouri Y, Nishijima H, Kawano H, Hirota F, Sakaguchi N, Morimoto J, Matsumoto M (2014) NF-kappaB-inducing kinase in thymic stroma establishes central tolerance by orchestrating cross-talk with not only thymocytes but also dendritic cells. J Immunol 193(9):4356–4367CrossRefGoogle Scholar
  109. Mouri Y, Ueda Y, Yamano T, Matsumoto M, Tsuneyama K, Kinashi T, Matsumoto M (2017) Mode of tolerance induction and requirement for aire are governed by the cell types that express self-antigen and those that present antigen. J Immunol 199(12):3959–3971PubMedCrossRefGoogle Scholar
  110. Murata S, Sasaki K, Kishimoto T, Niwa S, Hayashi H, Takahama Y, Tanaka K (2007) Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 316(5829):1349–1353PubMedCrossRefPubMedCentralGoogle Scholar
  111. 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(4):393–398PubMedPubMedCentralCrossRefGoogle Scholar
  112. Nakagawa T, Roth W, Wong P, Nelson A, Farr A, Deussing J, Villadangos JA, Ploegh H, Peters C, Rudensky AY (1998) Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. Science 280(5362):450–453PubMedCrossRefPubMedCentralGoogle Scholar
  113. Nedjic J, Aichinger M, Emmerich J, Mizushima N, Klein L (2008) Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455(7211):396–400PubMedCrossRefPubMedCentralGoogle Scholar
  114. Nehls M, Kyewski B, Messerle M, Waldschutz R, Schuddekopf K, Smith AJ, Boehm T (1996) Two genetically separable steps in the differentiation of thymic epithelium. Science 272(5263):886–889PubMedCrossRefPubMedCentralGoogle Scholar
  115. Niki S, Oshikawa K, Mouri Y, Hirota F, Matsushima A, Yano M, Han H, Bando Y, Izumi K, Matsumoto M, Nakayama KI, Kuroda N, Matsumoto M (2006) Alteration of intra-pancreatic target-organ specificity by abrogation of aire in NOD mice. J Clin Invest 116(5):1292–1301PubMedPubMedCentralCrossRefGoogle Scholar
  116. Nishijima H, Kitano S, Miyachi H, Morimoto J, Kawano H, Hirota F, Morita R, Mouri Y, Masuda K, Imoto I, Ikuta K, Matsumoto M (2015) Ectopic aire expression in the thymic cortex reveals inherent properties of aire as a tolerogenic factor within the medulla. J Immunol 195(10):4641–4649PubMedCrossRefPubMedCentralGoogle Scholar
  117. Nishijima H, Kajimoto T, Matsuoka Y, Mouri Y, Morimoto J, Matsumoto M, Kawano H, Nishioka Y, Uehara H, Izumi K, Tsuneyama K, Okazaki IM, Okazaki T, Hosomichi K, Shiraki A, Shibutani M, Mitsumori K, Matsumoto M (2018) Paradoxical development of polymyositis-like autoimmunity through augmented expression of autoimmune regulator (AIRE). J Autoimmun 86:75–92PubMedCrossRefGoogle Scholar
  118. Nishikawa Y, Hirota F, Yano M, Kitajima H, Miyazaki J, Kawamoto H, Mouri Y, Matsumoto M (2010) Biphasic aire expression in early embryos and in medullary thymic epithelial cells before end-stage terminal differentiation. J Exp Med 207(5):963–971PubMedPubMedCentralCrossRefGoogle Scholar
  119. Nishikawa Y, Nishijima H, Matsumoto M, Morimoto J, Hirota F, Takahashi S, Luche H, Fehling HJ, Mouri Y, Matsumoto M (2014) Temporal lineage tracing of aire-expressing cells reveals a requirement for aire in their maturation program. J Immunol 192(6):2585–2592PubMedCrossRefGoogle Scholar
  120. Nitta T, Murata S, Sasaki K, Fujii H, Ripen AM, Ishimaru N, Koyasu S, Tanaka K, Takahama Y (2010) Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. Immunity 32(1):29–40PubMedCrossRefGoogle Scholar
  121. O’Neill KE, Bredenkamp N, Tischner C, Vaidya HJ, Stenhouse FH, Peddie CD, Nowell CS, Gaskell T, Blackburn CC (2016) Foxn1 is dynamically regulated in thymic epithelial cells during embryogenesis and at the onset of thymic involution. PLoS One 11(3):e0151666PubMedPubMedCentralCrossRefGoogle Scholar
  122. Ohigashi I, Zuklys S, Sakata M, Mayer CE, Zhanybekova S, Murata S, Tanaka K, Hollander GA, Takahama Y (2013) Aire-expressing thymic medullary epithelial cells originate from beta5t-expressing progenitor cells. Proc Natl Acad Sci U S A 110(24):9885–9890PubMedPubMedCentralCrossRefGoogle Scholar
  123. Ohigashi I, Zuklys S, Sakata M, Mayer CE, Hamazaki Y, Minato N, Hollander GA, Takahama Y (2015) Adult thymic medullary epithelium is maintained and regenerated by lineage-restricted cells rather than bipotent progenitors. Cell Rep 13(7):1432–1443PubMedCrossRefGoogle Scholar
  124. Ohigashi I, Kozai M, Takahama Y (2016) Development and developmental potential of cortical thymic epithelial cells. Immunol Rev 271(1):10–22PubMedCrossRefPubMedCentralGoogle Scholar
  125. Olsen NJ, Olson G, Viselli SM, Gu X, Kovacs WJ (2001) Androgen receptors in thymic epithelium modulate thymus size and thymocyte development. Endocrinology 142(3):1278–1283PubMedCrossRefGoogle Scholar
  126. Onder L, Nindl V, Scandella E, Chai Q, Cheng HW, Caviezel-Firner S, Novkovic M, Bomze D, Maier R, Mair F, Ledermann B, Becher B, Waisman A, Ludewig B (2015) Alternative NF-kappaB signaling regulates mTEC differentiation from podoplanin-expressing precursors in the cortico-medullary junction. Eur J Immunol 45(8):2218–2231PubMedCrossRefGoogle Scholar
  127. Org T, Rebane A, Kisand K, Laan M, Haljasorg U, Andreson R, Peterson P (2009) AIRE activated tissue specific genes have histone modifications associated with inactive chromatin. Hum Mol Genet 18(24):4699–4710PubMedPubMedCentralCrossRefGoogle Scholar
  128. Otero DC, Baker DP, David M (2013) IRF7-dependent IFN-beta production in response to RANKL promotes medullary thymic epithelial cell development. J Immunol 190(7):3289–3298PubMedPubMedCentralCrossRefGoogle Scholar
  129. Papadopoulou AS, Dooley J, Linterman MA, Pierson W, Ucar O, Kyewski B, Zuklys S, Hollander GA, Matthys P, Gray DH, De Strooper B, Liston A (2011) The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-alpha receptor. Nat Immunol 13(2):181–187PubMedPubMedCentralCrossRefGoogle Scholar
  130. Perry JS, Lio CW, Kau AL, Nutsch K, Yang Z, Gordon JI, Murphy KM, Hsieh CS (2014) Distinct contributions of aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus. Immunity 41(3):414–426PubMedPubMedCentralCrossRefGoogle Scholar
  131. Petrie HT, Zuniga-Pflucker JC (2007) Zoned out: functional mapping of stromal signaling microenvironments in the thymus. Annu Rev Immunol 25:649–679CrossRefPubMedPubMedCentralGoogle Scholar
  132. Plotkin J, Prockop SE, Lepique A, Petrie HT (2003) Critical role for CXCR4 signaling in progenitor localization and T cell differentiation in the postnatal thymus. J Immunol 171(9):4521–4527PubMedCrossRefPubMedCentralGoogle Scholar
  133. Proietto AI, van Dommelen S, Zhou P, Rizzitelli A, D’Amico A, Steptoe RJ, Naik SH, Lahoud MH, Liu Y, Zheng P, Shortman K, Wu L (2008) Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc Natl Acad Sci U S A 105(50):19869–19874PubMedPubMedCentralCrossRefGoogle Scholar
  134. Revest JM, Suniara RK, Kerr K, Owen JJ, Dickson C (2001) Development of the thymus requires signaling through the fibroblast growth factor receptor R2-IIIb. J Immunol 167(4):1954–1961PubMedPubMedCentralCrossRefGoogle Scholar
  135. Ribeiro AR, Rodrigues PM, Meireles C, Di Santo JP, Alves NL (2013) Thymocyte selection regulates the homeostasis of IL-7-expressing thymic cortical epithelial cells in vivo. J Immunol 191(3):1200–1209PubMedCrossRefGoogle Scholar
  136. Ribeiro AR, Meireles C, Rodrigues PM, Alves NL (2014) Intermediate expression of CCRL1 reveals novel subpopulations of medullary thymic epithelial cells that emerge in the postnatal thymus. Eur J Immunol 44(10):2918–2924PubMedCrossRefPubMedCentralGoogle Scholar
  137. Riemann M, Andreas N, Fedoseeva M, Meier E, Weih D, Freytag H, Schmidt-Ullrich R, Klein U, Wang ZQ, Weih F (2017) Central immune tolerance depends on crosstalk between the classical and alternative NF-kappaB pathways in medullary thymic epithelial cells. J Autoimmun 81:56–67PubMedCrossRefPubMedCentralGoogle Scholar
  138. Rijhsinghani AG, Thompson K, Bhatia SK, Waldschmidt TJ (1996) Estrogen blocks early T cell development in the thymus. Am J Reprod Immunol 36(5):269–277PubMedCrossRefPubMedCentralGoogle Scholar
  139. Roberts NA, White AJ, Jenkinson WE, Turchinovich G, Nakamura K, Withers DR, McConnell FM, Desanti GE, Benezech C, Parnell SM, Cunningham AF, Paolino M, Penninger JM, Simon AK, Nitta T, Ohigashi I, Takahama Y, Caamano JH, Hayday AC, Lane PJ, Jenkinson EJ, Anderson G (2012) Rank signaling links the development of invariant gammadelta T cell progenitors and aire(+) medullary epithelium. Immunity 36(3):427–437PubMedPubMedCentralCrossRefGoogle Scholar
  140. Rode I, Martins VC, Kublbeck G, Maltry N, Tessmer C, Rodewald HR (2015) Foxn1 protein expression in the developing, aging, and regenerating thymus. J Immunol 195(12):5678–5687PubMedPubMedCentralCrossRefGoogle Scholar
  141. Rodewald HR, Paul S, Haller C, Bluethmann H, Blum C (2001) Thymus medulla consisting of epithelial islets each derived from a single progenitor. Nature 414(6865):763–768PubMedPubMedCentralCrossRefGoogle Scholar
  142. Rodrigues PM, Ribeiro AR, Perrod C, Landry JJM, Araujo L, Pereira-Castro I, Benes V, Moreira A, Xavier-Ferreira H, Meireles C, Alves NL (2017) Thymic epithelial cells require p53 to support their long-term function in thymopoiesis in mice. Blood 130(4):478–488PubMedCrossRefPubMedCentralGoogle Scholar
  143. Romano R, Palamaro L, Fusco A, Giardino G, Gallo V, Del Vecchio L, Pignata C (2013) FOXN1: a master regulator gene of thymic epithelial development program. Front Immunol 4:187PubMedPubMedCentralCrossRefGoogle Scholar
  144. Ropke C, Van Soest P, Platenburg PP, Van Ewijk W (1995) A common stem cell for murine cortical and medullary thymic epithelial cells? Dev Immunol 4(2):149–156PubMedPubMedCentralCrossRefGoogle Scholar
  145. Rossi FM, Corbel SY, Merzaban JS, Carlow DA, Gossens K, Duenas J, So L, Yi L, Ziltener HJ (2005) Recruitment of adult thymic progenitors is regulated by P-selectin and its ligand PSGL-1. Nat Immunol 6(6):626–634PubMedCrossRefPubMedCentralGoogle Scholar
  146. Rossi SW, Jenkinson WE, Anderson G, Jenkinson EJ (2006) Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 441(7096):988–991PubMedPubMedCentralCrossRefGoogle Scholar
  147. Rossi SW, Chidgey AP, Parnell SM, Jenkinson WE, Scott HS, Boyd RL, Jenkinson EJ, Anderson G (2007a) Redefining epithelial progenitor potential in the developing thymus. Eur J Immunol 37(9):2411–2418PubMedCrossRefGoogle Scholar
  148. Rossi SW, Kim MY, Leibbrandt A, Parnell SM, Jenkinson WE, Glanville SH, McConnell FM, Scott HS, Penninger JM, Jenkinson EJ, Lane PJ, Anderson G (2007b) RANK signals from CD4(+)3(-) inducer cells regulate development of aire-expressing epithelial cells in the thymic medulla. J Exp Med 204(6):1267–1272PubMedPubMedCentralCrossRefGoogle Scholar
  149. Rossi SW, Jeker LT, Ueno T, Kuse S, Keller MP, Zuklys S, Gudkov AV, Takahama Y, Krenger W, Blazar BR, Hollander GA (2007c) Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood 109(9):3803–3811PubMedPubMedCentralCrossRefGoogle Scholar
  150. Sakaguchi S (2004) Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562PubMedCrossRefPubMedCentralGoogle Scholar
  151. Sano S, Takahama Y, Sugawara T, Kosaka H, Itami S, Yoshikawa K, Miyazaki J, van Ewijk W, Takeda J (2001) Stat3 in thymic epithelial cells is essential for postnatal maintenance of thymic architecture and thymocyte survival. Immunity 15(2):261–273PubMedCrossRefPubMedCentralGoogle Scholar
  152. Satoh R, Kakugawa K, Yasuda T, Yoshida H, Sibilia M, Katsura Y, Levi B, Abramson J, Koseki Y, Koseki H, van Ewijk W, Hollander GA, Kawamoto H (2016) Requirement of Stat3 signaling in the postnatal development of thymic medullary epithelial cells. PLoS Genet 12(1):e1005776PubMedPubMedCentralCrossRefGoogle Scholar
  153. Schuddekopf K, Schorpp M, Boehm T (1996) The whn transcription factor encoded by the nude locus contains an evolutionarily conserved and functionally indispensable activation domain. Proc Natl Acad Sci U S A 93(18):9661–9664PubMedPubMedCentralCrossRefGoogle Scholar
  154. Schuster C, Gerold KD, Schober K, Probst L, Boerner K, Kim MJ, Ruckdeschel A, Serwold T, Kissler S (2015) The autoimmunity-associated gene CLEC16A modulates thymic epithelial cell autophagy and alters T cell selection. Immunity 42(5):942–952PubMedPubMedCentralCrossRefGoogle Scholar
  155. Scimone ML, Aifantis I, Apostolou I, von Boehmer H, von Andrian UH (2006) A multistep adhesion cascade for lymphoid progenitor cell homing to the thymus. Proc Natl Acad Sci U S A 103(18):7006–7011PubMedPubMedCentralCrossRefGoogle Scholar
  156. Sekai M, Hamazaki Y, Minato N (2014) Medullary thymic epithelial stem cells maintain a functional thymus to ensure lifelong central T cell tolerance. Immunity 41(5):753–761PubMedCrossRefPubMedCentralGoogle Scholar
  157. Sempowski GD, Hale LP, Sundy JS, Massey JM, Koup RA, Douek DC, Patel DD, Haynes BF (2000) Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy. J Immunol 164(4):2180–2187PubMedCrossRefGoogle Scholar
  158. Sempowski GD, Gooding ME, Liao HX, Le PT, Haynes BF (2002) T cell receptor excision circle assessment of thymopoiesis in aging mice. Mol Immunol 38(11):841–848PubMedCrossRefGoogle Scholar
  159. Senoo M, Pinto F, Crum CP, McKeon F (2007) p63 Is essential for the proliferative potential of stem cells in stratified epithelia. Cell 129(3):523–536PubMedCrossRefPubMedCentralGoogle Scholar
  160. Shakib S, Desanti GE, Jenkinson WE, Parnell SM, Jenkinson EJ, Anderson G (2009) Checkpoints in the development of thymic cortical epithelial cells. J Immunol 182(1):130–137PubMedCrossRefPubMedCentralGoogle Scholar
  161. Shanley DP, Aw D, Manley NR, Palmer DB (2009) An evolutionary perspective on the mechanisms of immunosenescence. Trends Immunol 30(7):374–381PubMedCrossRefPubMedCentralGoogle Scholar
  162. Shinkura R, Kitada K, Matsuda F, Tashiro K, Ikuta K, Suzuki M, Kogishi K, Serikawa T, Honjo T (1999) Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-kappa b-inducing kinase. Nat Genet 22(1):74–77PubMedCrossRefPubMedCentralGoogle Scholar
  163. Sitnik KM, Kotarsky K, White AJ, Jenkinson WE, Anderson G, Agace WW (2012) Mesenchymal cells regulate retinoic acid receptor-dependent cortical thymic epithelial cell homeostasis. J Immunol 188(10):4801–4809PubMedCrossRefPubMedCentralGoogle Scholar
  164. Smith KM, Olson DC, Hirose R, Hanahan D (1997) Pancreatic gene expression in rare cells of thymic medulla: evidence for functional contribution to T cell tolerance. Int Immunol 9(9):1355–1365PubMedCrossRefPubMedCentralGoogle Scholar
  165. Soleimanpour SA, Gupta A, Bakay M, Ferrari AM, Groff DN, Fadista J, Spruce LA, Kushner JA, Groop L, Seeholzer SH, Kaufman BA, Hakonarson H, Stoffers DA (2014) The diabetes susceptibility gene Clec16a regulates mitophagy. Cell 157(7):1577–1590PubMedPubMedCentralCrossRefGoogle Scholar
  166. Soza-Ried C, Bleul CC, Schorpp M, Boehm T (2008) Maintenance of thymic epithelial phenotype requires extrinsic signals in mouse and zebrafish. J Immunol 181(8):5272–5277PubMedPubMedCentralCrossRefGoogle Scholar
  167. Staples JE, Gasiewicz TA, Fiore NC, Lubahn DB, Korach KS, Silverstone AE (1999) Estrogen receptor alpha is necessary in thymic development and estradiol-induced thymic alterations. J Immunol 163(8):4168–4174PubMedPubMedCentralGoogle Scholar
  168. Steinmann GG, Klaus B, Muller-Hermelink HK (1985) The involution of the ageing human thymic epithelium is independent of puberty. A morphometric study. Scand J Immunol 22(5):563–575PubMedPubMedCentralCrossRefGoogle Scholar
  169. Sukseree S, Mildner M, Rossiter H, Pammer J, Zhang CF, Watanapokasin R, Tschachler E, Eckhart L (2012) Autophagy in the thymic epithelium is dispensable for the development of self-tolerance in a novel mouse model. PLoS One 7(6):e38933PubMedPubMedCentralCrossRefGoogle Scholar
  170. Sutherland JS, Goldberg GL, Hammett MV, Uldrich AP, Berzins SP, Heng TS, Blazar BR, Millar JL, Malin MA, Chidgey AP, Boyd RL (2005) Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol 175(4):2741–2753PubMedCrossRefGoogle Scholar
  171. Takada K, Van Laethem F, Xing Y, Akane K, Suzuki H, Murata S, Tanaka K, Jameson SC, Singer A, Takahama Y (2015) TCR affinity for thymoproteasome-dependent positively selecting peptides conditions antigen responsiveness in CD8(+) T cells. Nat Immunol 16(10):1069–1076PubMedPubMedCentralCrossRefGoogle Scholar
  172. Takada K, Kondo K, Takahama Y (2017) Generation of peptides that promote positive selection in the thymus. J Immunol 198(6):2215–2222PubMedCrossRefPubMedCentralGoogle Scholar
  173. Takahama Y (2006) Journey through the thymus: stromal guides for T-cell development and selection. Nat Rev Immunol 6(2):127–135CrossRefGoogle Scholar
  174. Takeoka Y, Chen SY, Yago H, Boyd R, Suehiro S, Shultz LD, Ansari AA, Gershwin ME (1996) The murine thymic microenvironment: changes with age. Int Arch Allergy Immunol 111(1):5–12PubMedCrossRefPubMedCentralGoogle Scholar
  175. Taub DD, Longo DL (2005) Insights into thymic aging and regeneration. Immunol Rev 205:72–93PubMedCrossRefGoogle Scholar
  176. Tsai PT, Lee RA, Wu H (2003) BMP4 acts upstream of FGF in modulating thymic stroma and regulating thymopoiesis. Blood 102(12):3947–3953PubMedPubMedCentralCrossRefGoogle Scholar
  177. Ulyanchenko S, O’Neill KE, Medley T, Farley AM, Vaidya HJ, Cook AM, Blair NF, Blackburn CC (2016) Identification of a bipotent epithelial progenitor population in the adult thymus. Cell Rep 14(12):2819–2832PubMedPubMedCentralCrossRefGoogle Scholar
  178. Van Vliet E, Melis M, Van Ewijk W (1984) Monoclonal antibodies to stromal cell types of the mouse thymus. Eur J Immunol 14(6):524–529PubMedPubMedCentralCrossRefGoogle Scholar
  179. Velardi E, Dudakov JA, van den Brink MR (2015) Sex steroid ablation: an immunoregenerative strategy for immunocompromised patients. Bone Marrow Transplant 50(Suppl 2):S77–S81PubMedPubMedCentralCrossRefGoogle Scholar
  180. Viselli SM, Olsen NJ, Shults K, Steizer G, Kovacs WJ (1995) Immunochemical and flow cytometric analysis of androgen receptor expression in thymocytes. Mol Cell Endocrinol 109(1):19–26PubMedCrossRefGoogle Scholar
  181. Wang X, Laan M, Bichele R, Kisand K, Scott HS, Peterson P (2012) Post-aire maturation of thymic medullary epithelial cells involves selective expression of keratinocyte-specific autoantigens. Front Immunol 3(March):19PubMedPubMedCentralGoogle Scholar
  182. Williams KM, Lucas PJ, Bare CV, Wang J, Chu YW, Tayler E, Kapoor V, Gress RE (2008) CCL25 increases thymopoiesis after androgen withdrawal. Blood 112(8):3255–3263PubMedPubMedCentralCrossRefGoogle Scholar
  183. Wong K, Lister NL, Barsanti M, Lim JM, Hammett MV, Khong DM, Siatskas C, Gray DH, Boyd RL, Chidgey AP (2014) Multilineage potential and self-renewal define an epithelial progenitor cell population in the adult thymus. Cell Rep 8(4):1198–1209PubMedCrossRefGoogle Scholar
  184. Yamano T, Nedjic J, Hinterberger M, Steinert M, Koser S, Pinto S, Gerdes N, Lutgens E, Ishimaru N, Busslinger M, Brors B, Kyewski B, Klein L (2015) Thymic B cells are licensed to present self antigens for central T cell tolerance induction. Immunity 42(6):1048–1061CrossRefGoogle Scholar
  185. Yang H, Youm YH, Sun Y, Rim JS, Galban CJ, Vandanmagsar B, Dixit VD (2009) Axin expression in thymic stromal cells contributes to an age-related increase in thymic adiposity and is associated with reduced thymopoiesis independently of ghrelin signaling. J Leukoc Biol 85(6):928–938PubMedPubMedCentralCrossRefGoogle Scholar
  186. Yang S, Fujikado N, Kolodin D, Benoist C, Mathis D (2015) Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science 348(6234):589–594PubMedPubMedCentralCrossRefGoogle Scholar
  187. 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(12):2827–2838PubMedPubMedCentralCrossRefGoogle Scholar
  188. Youm YH, Kanneganti TD, Vandanmagsar B, Zhu X, Ravussin A, Adijiang A, Owen JS, Thomas MJ, Francis J, Parks JS, Dixit VD (2012) The Nlrp3 inflammasome promotes age-related thymic demise and immunosenescence. Cell Rep 1(1):56–68PubMedCrossRefGoogle Scholar
  189. Zhu M, Chin RK, Christiansen PA, Lo JC, Liu X, Ware C, Siebenlist U, Fu YX (2006) NF-kappaB2 is required for the establishment of central tolerance through an aire-dependent pathway. J Clin Invest 116(11):2964–2971PubMedPubMedCentralCrossRefGoogle Scholar
  190. Zlotoff DA, Sambandam A, Logan TD, Bell JJ, Schwarz BA, Bhandoola A (2010) CCR7 and CCR9 together recruit hematopoietic progenitors to the adult thymus. Blood 115(10):1897–1905PubMedPubMedCentralCrossRefGoogle Scholar
  191. Zook EC, Krishack PA, Zhang S, Zeleznik-Le NJ, Firulli AB, Witte PL, Le PT (2011) Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells. Blood 118(22):5723–5731PubMedPubMedCentralCrossRefGoogle Scholar
  192. Zuklys S, Mayer CE, Zhanybekova S, Stefanski HE, Nusspaumer G, Gill J, Barthlott T, Chappaz S, Nitta T, Dooley J, Nogales-Cadenas R, Takahama Y, Finke D, Liston A, Blazar BR, Pascual-Montano A, Hollander GA (2012) MicroRNAs control the maintenance of thymic epithelia and their competence for T lineage commitment and thymocyte selection. J Immunol 189(8):3894–3904PubMedPubMedCentralCrossRefGoogle Scholar
  193. Zuklys S, Handel A, Zhanybekova S, Govani F, Keller M, Maio S, Mayer CE, Teh HY, Hafen K, Gallone G, Barthlott T, Ponting CP, Hollander GA (2016) Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells. Nat Immunol 17(10):1206–1215PubMedPubMedCentralCrossRefGoogle Scholar
  194. Zumer K, Saksela K, Peterlin BM (2013) The mechanism of tissue-restricted antigen gene expression by AIRE. J Immunol 190(6):2479–2482PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Minoru Matsumoto
    • 1
    • 2
  • Pedro M. Rodrigues
    • 3
    • 4
  • Laura Sousa
    • 3
  • Koichi Tsuneyama
    • 2
  • Mitsuru Matsumoto
    • 1
    Email author
  • Nuno L. Alves
    • 3
    • 4
    Email author
  1. 1.Division of Molecular Immunology, Institute for Enzyme ResearchTokushima UniversityTokushimaJapan
  2. 2.Department of Molecular and Environmental Pathology, Institute of Biomedical SciencesThe University of Tokushima Graduate SchoolTokushimaJapan
  3. 3.Instituto de Investigação e Inovação em SaúdeUniversidade do PortoPortoPortugal
  4. 4.Thymus Development and Function LaboratoryInstituto de Biologia Molecular e CelularPortoPortugal

Personalised recommendations