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Annual Review of Immunology

Volume 35, 2017

Thymic Epithelial Cells

Abstract

Intrathymic T cell development is a complex process that depends upon continuous guidance from thymus stromal cell microenvironments. The thymic epithelium within the thymic stroma comprises highly specialized cells with a high degree of anatomic, phenotypic, and functional heterogeneity. These properties are collectively required to bias thymocyte development toward production of self-tolerant and functionally competent T cells. The importance of thymic epithelial cells (TECs) is evidenced by clear links between their dysfunction and multiple diseases where autoimmunity and immunodeficiency are major components. Consequently, TECs are an attractive target for cell therapies to restore effective immune system function. The pathways and molecular regulators that control TEC development are becoming clearer, as are their influences on particular stages of T cell development. Here, we review both historical and the most recent advances in our understanding of the cellular and molecular mechanisms controlling TEC development, function, dysfunction, and regeneration.

Keyword(s): Aire, Foxp3, T cell, thymic epithelium, thymus, tolerance
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/content/journals/10.1146/annurev-immunol-051116-052320
2017-04-26
2024-04-19
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Literature Cited

  1. Boehm T, Swann JB. 1.  2014. Origin and evolution of adaptive immunity. Annu. Rev. Anim. Biosci. 2:259–83 [Google Scholar]
  2. Takahama Y. 2.  2006. Journey through the thymus: stromal guides for T-cell development and selection. Nat. Rev. Immunol. 6:2127–35 [Google Scholar]
  3. Rodewald H-R. 3.  2008. Thymus organogenesis. Annu. Rev. Immunol. 26:355–88 [Google Scholar]
  4. Chaudhry MS, Velardi E, Dudakov JA, van den Brink MRM. 4.  2016. Thymus: the next (re)generation. Immunol. Rev. 271:156–71 [Google Scholar]
  5. Rossi SW, Jenkinson WE, Anderson G, Jenkinson EJ. 5.  2006. Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 441:7096988–91 [Google Scholar]
  6. Bleul CC, Corbeaux T, Reuter A, Fisch P, Mönting JS, Boehm T. 6.  2006. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 441:7096992–96 [Google Scholar]
  7. Mayer CE, Žuklys S, Zhanybekova S, Ohigashi I, Teh H-Y. 7.  et al. 2016. Dynamic spatio-temporal contribution of single β5t+ cortical epithelial precursors to the thymus medulla. Eur. J. Immunol. 46:4846–56 [Google Scholar]
  8. Ohigashi I, Zuklys S, Sakata M, Mayer CE, Hamazaki Y. 8.  et al. 2015. Adult thymic medullary epithelium is maintained and regenerated by lineage-restricted cells rather than bipotent progenitors. Cell Rep 13:71432–43 [Google Scholar]
  9. Ribeiro AR, Rodrigues PM, Meireles C, Di Santo JP, Alves NL. 9.  2013. Thymocyte selection regulates the homeostasis of IL-7-expressing thymic cortical epithelial cells in vivo. J. Immunol. 191:31200–9 [Google Scholar]
  10. Baik S, Jenkinson EJ, Lane PJL, Anderson G, Jenkinson WE. 10.  2013. Generation of both cortical and AIRE+ medullary thymic epithelial compartments from CD205+ progenitors. Eur. J. Immunol. 43:3589–94 [Google Scholar]
  11. Alves NL, Takahama Y, Ohigashi I, Ribeiro AR, Baik S. 11.  et al. 2014. Serial progression of cortical and medullary thymic epithelial microenvironments. Eur. J. Immunol. 44:116–22 [Google Scholar]
  12. Gill J, Malin M, Holländer GA, Boyd R. 12.  2002. Generation of a complete thymic microenvironment by MTS24+ thymic epithelial cells. Nat. Immunol. 3:7635–42 [Google Scholar]
  13. Bennett AR, Farley A, Blair NF, Gordon J, Sharp L, Blackburn CC. 13.  2002. Identification and characterization of thymic epithelial progenitor cells. Immunity 16:6803–14 [Google Scholar]
  14. Depreter MGL, Blair NF, Gaskell TL, Nowell CS, Davern K. 14.  et al. 2008. Identification of Plet-1 as a specific marker of early thymic epithelial progenitor cells. PNAS 105:3961–66 [Google Scholar]
  15. Rossi SW, Chidgey AP, Parnell SM, Jenkinson WE, Scott HS. 15.  et al. 2007. Redefining epithelial progenitor potential in the developing thymus. Eur. J. Immunol. 37:92411–18 [Google Scholar]
  16. Ucar A, Ucar O, Klug P, Matt S, Brunk F. 16.  et al. 2014. Adult thymus contains FoxN1− epithelial stem cells that are bipotent for medullary and cortical thymic epithelial lineages. Immunity 41:2257–69 [Google Scholar]
  17. Wong K, Lister NL, Barsanti M, Lim JMC, Hammett MV. 17.  et al. 2014. Multilineage potential and self-renewal define an epithelial progenitor cell population in the adult thymus. Cell Rep 8:41198–209 [Google Scholar]
  18. Ulyanchenko S, O'Neill KE, Medley T, Farley AM, Vaidya HJ. 18.  et al. 2016. Identification of a bipotent epithelial progenitor population in the adult thymus. Cell Rep 14:122819–32 [Google Scholar]
  19. Rodewald HR, Paul S, Haller C, Bluethmann H, Blum C. 19.  2001. Thymus medulla consisting of epithelial islets each derived from a single progenitor. Nature 414:6865763–68 [Google Scholar]
  20. Shakib S, Desanti GE, Jenkinson WE, Parnell SM, Jenkinson EJ, Anderson G. 20.  2009. Checkpoints in the development of thymic cortical epithelial cells. J. Immunol. 182:1130–37 [Google Scholar]
  21. Rode I, Boehm T. 21.  2012. Regenerative capacity of adult cortical thymic epithelial cells. PNAS 109:93463–68 [Google Scholar]
  22. Gray D, Abramson J, Benoist C, Mathis D. 22.  2007. Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire. J. Exp. Med. 204:112521–28 [Google Scholar]
  23. Rossi SW, Kim M-Y, Leibbrandt A, Parnell SM, Jenkinson WE. 23.  et al. 2007. RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J. Exp. Med. 204:61267–72 [Google Scholar]
  24. Lkhagvasuren E, Sakata M, Ohigashi I, Takahama Y. 24.  2013. Lymphotoxin β receptor regulates the development of CCL21-expressing subset of postnatal medullary thymic epithelial cells. J. Immunol. 190:105110–17 [Google Scholar]
  25. Hamazaki Y, Fujita H, Kobayashi T, Choi Y, Scott HS. 25.  et al. 2007. Medullary thymic epithelial cells expressing Aire represent a unique lineage derived from cells expressing claudin. Nat. Immunol. 8:3304–11 [Google Scholar]
  26. Sekai M, Hamazaki Y, Minato N. 26.  2014. Medullary thymic epithelial stem cells maintain a functional thymus to ensure lifelong central T cell tolerance. Immunity 41:5753–61 [Google Scholar]
  27. Baik S, Sekai M, Hamazaki Y, Jenkinson WE, Anderson G. 27.  2016. Relb acts downstream of medullary thymic epithelial stem cells and is essential for the emergence of RANK+ medullary epithelial progenitors. Eur. J. Immunol. 46:4857–62 [Google Scholar]
  28. Nowell CS, Bredenkamp N, Tetélin S, Jin X, Tischner C. 28.  et al. 2011. Foxn1 regulates lineage progression in cortical and medullary thymic epithelial cells but is dispensable for medullary sublineage divergence. PLOS Genet 7:11e1002348 [Google Scholar]
  29. Akiyama N, Takizawa N, Miyauchi M, Yanai H, Tateishi R. 29.  et al. 2016. Identification of embryonic precursor cells that differentiate into thymic epithelial cells expressing autoimmune regulator. J. Exp. Med. 213:1441–58 [Google Scholar]
  30. Hikosaka Y, Nitta T, Ohigashi I, Yano K, Ishimaru N. 30.  et al. 2008. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 29:3438–50 [Google Scholar]
  31. Akiyama T, Shimo Y, Yanai H, Qin J, Ohshima D. 31.  et al. 2008. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29:3423–37 [Google Scholar]
  32. Mouri Y, Yano M, Shinzawa M, Shimo Y, Hirota F. 32.  et al. 2011. Lymphotoxin signal promotes thymic organogenesis by eliciting rank expression in the embryonic thymic stroma. J. Immunol. 186:95047–57 [Google Scholar]
  33. Onder L, Nindl V, Scandella E, Chai Q, Cheng H-W. 33.  et al. 2015. Alternative NF-κB signaling regulates mTEC differentiation from podoplanin-expressing presursors in the cortico-medullary junction. Eur. J. Immunol. 45:82218–31 [Google Scholar]
  34. Manley NR, Condie BG. 34.  2010. Transcriptional regulation of thymus organogenesis and thymic epithelial cell differentiation. Prog. Mol. Biol. Transl. Sci. 92:10103–20 [Google Scholar]
  35. Goldfarb Y, Kadouri N, Levi B, Sela A, Herzig Y. 35.  et al. 2016. HDAC3 is a master regulator of mTEC development. Cell Rep 15:3651–65 [Google Scholar]
  36. Nehls M, Kyewski B, Messerle M, Waldschütz R, Schüddekopf K. 36.  et al. 1996. Two genetically separable steps in the differentiation of thymic epithelium. Science 272:5263886–89 [Google Scholar]
  37. Cheng L, Guo J, Sun L, Fu J, Barnes PF. 37.  et al. 2010. Postnatal tissue-specific disruption of transcription factor FoxN1 triggers acute thymic atrophy. J. Biol. Chem. 285:85836–47 [Google Scholar]
  38. Rode I, Martins VC, Küblbeck G, Maltry N, Tessmer C, Rodewald H-R. 38.  2015. Foxn1 protein expression in the developing, aging, and regenerating thymus. J. Immunol. 195:125678–87 [Google Scholar]
  39. Zuklys S, Handel A, Zhanybekova S, Govani F, Keller M. 39.  et al. 2016. Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells. Nat. Immunol. 17:1206–15 [Google Scholar]
  40. Bleul CC, Boehm T. 40.  2005. BMP signaling is required for normal thymus development. J. Immunol. 175:85213–21 [Google Scholar]
  41. Gordon J, Patel SR, Mishina Y, Manley NR. 41.  2010. Evidence for an early role for BMP4 signaling in thymus and parathyroid morphogenesis. Dev. Biol. 339:1141–54 [Google Scholar]
  42. Balciunaite G, Keller MP, Balciunaite E, Piali L, Zuklys S. 42.  et al. 2002. Wnt glycoproteins regulate the expression of FoxN1, the gene defective in nude mice. Nat. Immunol. 3:111102–8 [Google Scholar]
  43. Heinonen KM, Vanegas JR, Brochu S, Shan J, Vainio SJ, Perreault C. 43.  2011. Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors. Blood 118:195163–73 [Google Scholar]
  44. Liang C-C, You L-R, Yen JJY, Liao N-S, Yang-Yen H-F, Chen C-M. 44.  2013. Thymic epithelial β-catenin is required for adult thymic homeostasis and function. Immunol. Cell Biol. 91:8511–23 [Google Scholar]
  45. Osada M, Jardine L, Misir R, Andl T, Millar SE, Pezzano M. 45.  2010. DKK1 mediated inhibition of Wnt signaling in postnatal mice leads to loss of TEC progenitors and thymic degeneration. PLOS ONE 5:2e9062 [Google Scholar]
  46. Zuklys S, Gill J, Keller MP, Hauri-Hohl M, Zhanybekova S. 46.  et al. 2009. Stabilized beta-catenin in thymic epithelial cells blocks thymus development and function. J. Immunol. 182:52997–3007 [Google Scholar]
  47. Wang H-X, Shin J, Wang S, Gorentla B, Lin X. 47.  et al. 2016. mTORC1 in thymic epithelial cells is critical for thymopoiesis, T-cell generation, and temporal control of γδT17 development and TCRγ/δ recombination. PLOS Biol 14:2e1002370 [Google Scholar]
  48. Wang H-X, Cheng JS, Chu S, Qiu Y-R, Zhong X-P. 48.  2016. mTORC2 in thymic epithelial cells controls thymopoiesis and T cell development. J. Immunol. 197:1141–50 [Google Scholar]
  49. Candi E, Rufini A, Terrinoni A, Giamboi-Miraglia A, Lena AM. 49.  et al. 2007. ΔNp63 regulates thymic development through enhanced expression of FgfR2 and Jag2. PNAS 104:2911999–2004 [Google Scholar]
  50. Liu B, Liu Y-F, Du Y-R, Mardaryev AN, Yang W. 50.  et al. 2013. Cbx4 regulates the proliferation of thymic epithelial cells and thymus function. Development 140:4780–88 [Google Scholar]
  51. Papadopoulou AS, Dooley J, Linterman MA, Pierson W, Ucar O. 51.  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. 13:2181–87 [Google Scholar]
  52. Zuklys S, Mayer CE, Zhanybekova S, Stefanski HE, Nusspaumer G. 52.  et al. 2012. microRNAs control the maintenance of thymic epithelia and their competence for T lineage commitment and thymocyte selection. J. Immunol. 189:83894–904 [Google Scholar]
  53. Revest JM, Suniara RK, Kerr K, Owen JJ, Dickson C. 53.  2001. Development of the thymus requires signaling through the fibroblast growth factor receptor R2-IIIb. J. Immunol. 167:41954–61 [Google Scholar]
  54. Dooley J, Erickson M, Larochelle WJ, Gillard GO, Farr AG. 54.  2007. FgfR2IIIb signaling regulates thymic epithelial differentiation. Dev. Dyn. 236:123459–71 [Google Scholar]
  55. Saldaña JI, Solanki A, Lau C-I, Sahni H, Ross S. 55.  et al. 2016. Sonic Hedgehog regulates thymic epithelial cell differentiation. J. Autoimmun. 68:86–97 [Google Scholar]
  56. Parent AV, Russ HA, Khan IS, LaFlam TN, Metzger TC. 56.  et al. 2013. Generation of functional thymic epithelium from human embryonic stem cells that supports host T cell development. Cell Stem Cell 13:2219–29 [Google Scholar]
  57. Sun X, Xu J, Lu H, Liu W, Miao Z. 57.  et al. 2013. Directed differentiation of human embryonic stem cells into thymic epithelial progenitor-like cells reconstitutes the thymic microenvironment in vivo. Cell Stem Cell 13:2230–36 [Google Scholar]
  58. Su M, Hu R, Jin J, Yan Y, Song Y. 58.  et al. 2015. Efficient in vitro generation of functional thymic epithelial progenitors from human embryonic stem cells. Sci. Rep. 5:9882 [Google Scholar]
  59. Sitnik KM, Kotarsky K, White AJ, Jenkinson WE, Anderson G, Agace WW. 59.  2012. Mesenchymal cells regulate retinoic acid receptor-dependent cortical thymic epithelial cell homeostasis. J. Immunol. 188:104801–9 [Google Scholar]
  60. Masuda K, Germeraad WTV, Satoh R, Itoi M, Ikawa T. 60.  et al. 2009. Notch activation in thymic epithelial cells induces development of thymic microenvironments. Mol. Immunol. 46:8–91756–67 [Google Scholar]
  61. Boehm T, Scheu S, Pfeffer K, Bleul CC. 61.  2003. Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTβR. J. Exp. Med. 198:5757–69 [Google Scholar]
  62. Satoh R, Kakugawa K, Yasuda T, Yoshida H, Sibilia M. 62.  et al. 2016. Requirement of Stat3 signaling in the postnatal development of thymic medullary epithelial cells. PLOS Genet 12:1e1005776 [Google Scholar]
  63. Metzger TC, Khan IS, Gardner JM, Mouchess ML, Johannes KP. 63.  et al. 2013. Lineage tracing and cell ablation identify a post-Aire-expressing thymic epithelial cell population. Cell Rep 5:1166–79 [Google Scholar]
  64. Yano M, Kuroda N, Han H, Meguro-Horike M, Nishikawa Y. 64.  et al. 2008. Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance. J. Exp. Med. 205:122827–38 [Google Scholar]
  65. Kanariou M, Huby R, Ladyman H, Colic M, Sivolapenko G. 65.  et al. 1989. Immunosuppression with cyclosporin A alters the thymic microenvironment. Clin. Exp. Immunol. 78:2263–70 [Google Scholar]
  66. Shores EW, Van Ewijk W, Singer A. 66.  1991. Disorganization and restoration of thymic medullary epithelial cells in T cell receptor-negative scid mice: evidence that receptor-bearing lymphocytes influence maturation of the thymic microenvironment. Eur. J. Immunol. 21:71657–61 [Google Scholar]
  67. Holländer GA, Wang B, Nichogiannopoulou A, Platenburg PP, van Ewijk W. 67.  et al. 1995. Developmental control point in induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature 373:6512350–53 [Google Scholar]
  68. Palmer DB, Viney JL, Ritter MA, Hayday AC, Owen MJ. 68.  1993. Expression of the αβ T-cell receptor is necessary for the generation of the thymic medulla. Dev. Immunol. 3:3175–79 [Google Scholar]
  69. Velardi E, Tsai JJ, Holland AM, Wertheimer T, Yu VWC. 69.  et al. 2014. Sex steroid blockade enhances thymopoiesis by modulating notch signaling. J. Exp. Med. 211:122341–49 [Google Scholar]
  70. Fiorini E, Ferrero I, Merck E, Favre S, Pierres M. 70.  et al. 2008. Cutting edge: Thymic crosstalk regulates delta-like 4 expression on cortical epithelial cells. J. Immunol. 181:128199–203 [Google Scholar]
  71. Alves NL, Huntington ND, Mention J-J, Richard-Le Goff O, Di Santo JP. 71.  2010. Cutting edge: A thymocyte-thymic epithelial cell cross-talk dynamically regulates intrathymic IL-7 expression in vivo. J. Immunol. 184:115949–53 [Google Scholar]
  72. Anderson G, Takahama Y. 72.  2012. Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol 33:6256–63 [Google Scholar]
  73. Chin RK, Lo JC, Kim O, Blink SE, Christiansen PA. 73.  et al. 2003. Lymphotoxin pathway directs thymic Aire expression. Nat. Immunol. 4:1121–27 [Google Scholar]
  74. Venanzi ES, Gray DHD, Benoist C, Mathis D. 74.  2007. Lymphotoxin pathway and Aire influences on thymic medullary epithelial cells are unconnected. J. Immunol. 179:95693–700 [Google Scholar]
  75. Martins VC, Boehm T, Bleul CC. 75.  2008. LTβR signaling does not regulate Aire-dependent transcripts in medullary thymic epithelial cells. J. Immunol. 181:1400–7 [Google Scholar]
  76. White AJ, Nakamura K, Jenkinson WE, Saini M, Sinclair C. 76.  et al. 2010. Lymphotoxin signals from positively selected thymocytes regulate the terminal differentiation of medullary thymic epithelial cells. J. Immunol. 185:84769–76 [Google Scholar]
  77. McCarthy NI, Cowan JE, Nakamura K, Bacon A, Baik S. 77.  et al. 2015. Osteoprotegerin-mediated homeostasis of Rank+ thymic epithelial cells does not limit Foxp3+ regulatory T cell development. J. Immunol. 195:62675–82 [Google Scholar]
  78. Desanti GE, Cowan JE, Baik S, Parnell SM, White AJ. 78.  et al. 2012. Developmentally regulated availability of RANKL and CD40 ligand reveals distinct mechanisms of fetal and adult cross-talk in the thymus medulla. J. Immunol. 189:125519–26 [Google Scholar]
  79. Irla M, Hugues S, Gill J, Nitta T, Hikosaka Y. 79.  et al. 2008. Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity. Immunity 29:3451–63 [Google Scholar]
  80. Roberts NA, White AJ, Jenkinson WE, Turchinovich G, Nakamura K. 80.  et al. 2012. Rank signaling links the development of invariant γδ T cell progenitors and Aire+ medullary epithelium. Immunity 36:3427–37 [Google Scholar]
  81. White AJ, Jenkinson WE, Cowan JE, Parnell SM, Bacon A. 81.  et al. 2014. An essential role for medullary thymic epithelial cells during the intrathymic development of invariant NKT cells. J. Immunol. 192:62659–66 [Google Scholar]
  82. Guerau-de-Arellano M, Martinic M, Benoist C, Mathis D. 82.  2009. Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity. J. Exp. Med. 206:61245–52 [Google Scholar]
  83. Zhang SL, Bhandoola A. 83.  2014. Trafficking to the thymus. Curr. Top. Microbiol. Immunol. 373:87–111 [Google Scholar]
  84. Gossens K, Naus S, Corbel SY, Lin S, Rossi FMV. 84.  et al. 2009. Thymic progenitor homing and lymphocyte homeostasis are linked via S1P-controlled expression of thymic P-selectin/CCL25. J. Exp. Med. 206:4761–78 [Google Scholar]
  85. Bleul CC, Boehm T. 85.  2000. Chemokines define distinct microenvironments in the developing thymus. Eur. J. Immunol. 30:123371–79 [Google Scholar]
  86. Jenkinson WE, Rossi SW, Parnell SM, Agace WW, Takahama Y. 86.  et al. 2007. Chemokine receptor expression defines heterogeneity in the earliest thymic migrants. Eur. J. Immunol. 37:82090–96 [Google Scholar]
  87. Plotkin J, Prockop SE, Lepique A, Petrie HT. 87.  2003. Critical role for CXCR4 signaling in progenitor localization and T cell differentiation in the postnatal thymus. J. Immunol. 171:94521–27 [Google Scholar]
  88. Ueno T, Hara K, Willis MS, Malin MA, Höpken UE. 88.  et al. 2002. Role for CCR7 ligands in the emigration of newly generated T lymphocytes from the neonatal thymus. Immunity 16:2205–18 [Google Scholar]
  89. Lucas B, White AJ, Ulvmar MH, Nibbs RJB, Sitnik KM. 89.  et al. 2015. CCRL1/ACKR4 is expressed in key thymic microenvironments but is dispensable for T lymphopoiesis at steady state in adult mice. Eur. J. Immunol. 45:2574–83 [Google Scholar]
  90. Griffith AV, Fallahi M, Nakase H, Gosink M, Young B, Petrie HT. 90.  2009. Spatial mapping of thymic stromal microenvironments reveals unique features influencing T lymphoid differentiation. Immunity 31:6999–1009 [Google Scholar]
  91. Buono M, Facchini R, Matsuoka S, Thongjuea S, Waithe D. 91.  et al. 2016. A dynamic niche provides Kit ligand in a stage-specific manner to the earliest thymocyte progenitors. Nat. Cell Biol. 18:2157–67 [Google Scholar]
  92. Alves NL, Richard-Le Goff O, Huntington ND, Sousa AP, Ribeiro VSG. 92.  et al. 2009. Characterization of the thymic IL-7 niche in vivo. PNAS 106:51512–17 [Google Scholar]
  93. Hozumi K, Mailhos C, Negishi N, Hirano K, Yahata T. 93.  et al. 2008. Delta-like 4 is indispensable in thymic environment specific for T cell development. J. Exp. Med. 205:112507–13 [Google Scholar]
  94. Koch U, Fiorini E, Benedito R, Besseyrias V, Schuster-Gossler K. 94.  et al. 2008. Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. J. Exp. Med. 205:112515–23 [Google Scholar]
  95. Ferrero I, Koch U, Claudinot S, Favre S, Radtke F. 95.  et al. 2013. DL4-mediated Notch signaling is required for the development of fetal αβ and γδ T cells. Eur. J. Immunol. 43:112845–53 [Google Scholar]
  96. Nedjic J, Aichinger M, Emmerich J, Mizushima N, Klein L. 96.  2008. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455:7211396–400 [Google Scholar]
  97. Jenkinson WE, Nakamura K, White AJ, Jenkinson EJ, Anderson G. 97.  2012. Normal T cell selection occurs in CD205-deficient thymic microenvironments. PLOS ONE 7:12e53416 [Google Scholar]
  98. Honey K, Nakagawa T, Peters C, Rudensky A. 98.  2002. Cathepsin l regulates CD4+ T cell selection independently of its effect on invariant chain: a role in the generation of positively selecting peptide ligands. J. Exp. Med. 195:101349–58 [Google Scholar]
  99. Gommeaux J, Grégoire C, Nguessan P, Richelme M, Malissen M. 99.  et al. 2009. Thymus-specific serine protease regulates positive selection of a subset of CD4+ thymocytes. Eur. J. Immunol. 39:4956–64 [Google Scholar]
  100. Murata S, Sasaki K, Kishimoto T, Niwa S-I, Hayashi H. 100.  et al. 2007. Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 316:58291349–53 [Google Scholar]
  101. Nitta T, Murata S, Sasaki K, Fujii H, Ripen AM. 101.  et al. 2010. Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. Immunity 32:129–40 [Google Scholar]
  102. Takada K, Van Laethem F, Xing Y, Akane K, Suzuki H. 102.  et al. 2015. TCR affinity for thymoproteasome-dependent positively selecting peptides conditions antigen responsiveness in CD8+ T cells. Nat. Immunol. 16:101069–76 [Google Scholar]
  103. Sasaki K, Takada K, Ohte Y, Kondo H, Sorimachi H. 103.  et al. 2015. Thymoproteasomes produce unique peptide motifs for positive selection of CD8+ T cells. Nat. Commun. 6:7484 [Google Scholar]
  104. Wekerle H, Ketelsen UP. 104.  1980. Thymic nurse cells—Ia-bearing epithelium involved in T-lymphocyte differentiation?. Nature 283:5745402–4 [Google Scholar]
  105. Nakagawa Y, Ohigashi I, Nitta T, Sakata M, Tanaka K. 105.  et al. 2012. Thymic nurse cells provide microenvironment for secondary T cell receptor α rearrangement in cortical thymocytes. PNAS 109:5020572–77 [Google Scholar]
  106. Stritesky GL, Xing Y, Erickson JR, Kalekar LA, Wang X. 106.  et al. 2013. Murine thymic selection quantified using a unique method to capture deleted T cells. PNAS 110:124679–84 [Google Scholar]
  107. McCaughtry TM, Baldwin TA, Wilken MS, Hogquist KA. 107.  2008. Clonal deletion of thymocytes can occur in the cortex with no involvement of the medulla. J. Exp. Med. 205:112575–84 [Google Scholar]
  108. Xing Y, Wang X, Jameson SC, Hogquist KA. 108.  2016. Late stages of T cell maturation in the thymus involve NF-κB and tonic type I interferon signaling. Nat. Immunol. 17:5565–73 [Google Scholar]
  109. Klein L, Kyewski B, Allen PM, Hogquist KA. 109.  2014. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat. Rev. Immunol. 14:6377–91 [Google Scholar]
  110. Kyewski B, Klein L. 110.  2006. A central role for central tolerance. Annu. Rev. Immunol. 24:571–606 [Google Scholar]
  111. Taniguchi RT, DeVoss JJ, Moon JJ, Sidney J, Sette A. 111.  et al. 2012. Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection. PNAS 109:207847–52 [Google Scholar]
  112. Lei Y, Ripen AM, Ishimaru N, Ohigashi I, Nagasawa T. 112.  et al. 2011. Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. J. Exp. Med. 208:2383–94 [Google Scholar]
  113. Mouri Y, Nishijima H, Kawano H, Hirota F, Sakaguchi N. 113.  et al. 2014. NF-κB-inducing kinase in thymic stroma establishes central tolerance by orchestrating cross-talk with not only thymocytes but also dendritic cells. J. Immunol. 193:94356–67 [Google Scholar]
  114. Baba T, Nakamoto Y, Mukaida N. 114.  2009. Crucial contribution of thymic Sirpα+ conventional dendritic cells to central tolerance against blood-borne antigens in a CCR2-dependent manner. J. Immunol. 183:53053–63 [Google Scholar]
  115. Hadeiba H, Lahl K, Edalati A, Oderup C, Habtezion A. 115.  et al. 2012. Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. Immunity 36:3438–50 [Google Scholar]
  116. Davis MM. 116.  2015. Not-so-negative selection. Immunity 43:5833–35 [Google Scholar]
  117. Malhotra D, Linehan JL, Dileepan T, Lee YJ, Purtha WE. 117.  et al. 2016. Tolerance is established in polyclonal CD4+ T cells by distinct mechanisms, according to self-peptide expression patterns. Nat. Immunol. 17:2187–95 [Google Scholar]
  118. Legoux FP, Lim J-B, Cauley AW, Dikiy S, Ertelt J. 118.  et al. 2015. CD4+ T cell tolerance to tissue-restricted self antigens is mediated by antigen-specific regulatory T cells rather than deletion. Immunity 43:5896–908 [Google Scholar]
  119. Aschenbrenner K, D'Cruz LM, Vollmann EH, Hinterberger M, Emmerich J. 119.  et al. 2007. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat. Immunol. 8:4351–58 [Google Scholar]
  120. Wirnsberger G, Hinterberger M, Klein L. 120.  2011. Regulatory T-cell differentiation versus clonal deletion of autoreactive thymocytes. Immunol. Cell Biol. 89:145–53 [Google Scholar]
  121. Coquet JM, Ribot JC, Bąbała N, Middendorp S, van der Horst G. 121.  et al. 2013. Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway. J. Exp. Med. 210:4715–28 [Google Scholar]
  122. Cowan JE, Parnell SM, Nakamura K, Caamano JH, Lane PJL. 122.  et al. 2013. The thymic medulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development. J. Exp. Med. 210:4675–81 [Google Scholar]
  123. Tai X, Erman B, Alag A, Mu J, Kimura M. 123.  et al. 2013. Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity 38:61116–28 [Google Scholar]
  124. Lio C-WJ, Hsieh C-S. 124.  2008. A two-step process for thymic regulatory T cell development. Immunity 28:1100–11 [Google Scholar]
  125. Mahmud SA, Manlove LS, Schmitz HM, Xing Y, Wang Y. 125.  et al. 2014. Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat. Immunol. 15:5473–81 [Google Scholar]
  126. Hale JS, Fink PJ. 126.  2009. Back to the thymus: Peripheral T cells come home. Immunol. Cell Biol. 87:158–64 [Google Scholar]
  127. Kirberg J, Bosco N, Deloulme J-C, Ceredig R, Agenès F. 127.  2008. Peripheral T lymphocytes recirculating back into the thymus can mediate thymocyte positive selection. J. Immunol. 181:21207–14 [Google Scholar]
  128. McCaughtry TM, Wilken MS, Hogquist KA. 128.  2007. Thymic emigration revisited. J. Exp. Med. 204:112513–20 [Google Scholar]
  129. Cowan JE, McCarthy NI, Anderson G. 129.  2016. CCR7 controls thymus recirculation, but not production and emigration, of Foxp3+ T cells. Cell Rep 14:51041–48 [Google Scholar]
  130. Hauri-Hohl M, Zuklys S, Holländer GA, Ziegler SF. 130.  2014. A regulatory role for TGF-β signaling in the establishment and function of the thymic medulla. Nat. Immunol. 15:6554–61 [Google Scholar]
  131. Akiyama N, Shinzawa M, Miyauchi M, Yanai H, Tateishi R. 131.  et al. 2014. Limitation of immune tolerance-inducing thymic epithelial cell development by Spi-B-mediated negative feedback regulation. J. Exp. Med. 211:122425–38 [Google Scholar]
  132. Thiault N, Darrigues J, Adoue V, Gros M, Binet B. 132.  et al. 2015. Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors. Nat. Immunol. 16:6628–34 [Google Scholar]
  133. Weist BM, Kurd N, Boussier J, Chan SW, Robey EA. 133.  2015. Thymic regulatory T cell niche size is dictated by limiting IL-2 from antigen-bearing dendritic cells and feedback competition. Nat. Immunol. 16:6635–41 [Google Scholar]
  134. Stritesky GL, Jameson SC, Hogquist KA. 134.  2012. Selection of self-reactive T cells in the thymus. Annu. Rev. Immunol. 30:95–114 [Google Scholar]
  135. Bendelac A. 135.  1995. Positive selection of mouse NK1+ T cells by CD1-expressing cortical thymocytes. J. Exp. Med. 182:62091–96 [Google Scholar]
  136. Nitta T, Muro R, Shimizu Y, Nitta S, Oda H. 136.  et al. 2015. The thymic cortical epithelium determines the TCR repertoire of IL-17-producing γδT cells. EMBO Rep 16:5638–53 [Google Scholar]
  137. Kappler JW, Roehm N, Marrack P. 137.  1987. T cell tolerance by clonal elimination in the thymus. Cell 49:2273–80 [Google Scholar]
  138. Kisielow P, Blüthmann H, Staerz UD, Steinmetz M, von Boehmer H. 138.  1988. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature 333:6175742–46 [Google Scholar]
  139. Miller JF, Morahan G, Allison J. 139.  1989. Extrathymic acquisition of tolerance by T lymphocytes. Cold Spring Harb. Symp. Quant. Biol. 54:807–13 [Google Scholar]
  140. Linsk R, Gottesman M, Pernis B. 140.  1989. Are tissues a patch quilt of ectopic gene expression?. Science 246:4927261 [Google Scholar]
  141. Ohki H, Martin C, Corbel C, Coltey M, Le Douarin NM. 141.  1987. Tolerance induced by thymic epithelial grafts in birds. Science 237:48181032–35 [Google Scholar]
  142. Kirchner T, Tzartos S, Hoppe F, Schalke B, Wekerle H, Müller-Hermelink HK. 142.  1988. Pathogenesis of myasthenia gravis: acetylcholine receptor-related antigenic determinants in tumor-free thymuses and thymic epithelial tumors. Am. J. Pathol. 130:2268–80 [Google Scholar]
  143. Jolicoeur C, Hanahan D, Smith KM. 143.  1994. T-cell tolerance toward a transgenic β-cell antigen and transcription of endogenous pancreatic genes in thymus. PNAS 91:146707–11 [Google Scholar]
  144. Sospedra M, Ferrer-Francesch X, Domínguez O, Juan M, Foz-Sala M, Pujol-Borrell R. 144.  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. 161:115918–29 [Google Scholar]
  145. Smith KM, Olson DC, Hirose R, Hanahan D. 145.  1997. Pancreatic gene expression in rare cells of thymic medulla: evidence for functional contribution to T cell tolerance. Int. Immunol. 9:91355–65 [Google Scholar]
  146. Klein L, Klein T, Rüther U, Kyewski B. 146.  1998. CD4 T cell tolerance to human C-reactive protein, an inducible serum protein, is mediated by medullary thymic epithelium. J. Exp. Med. 188:15–16 [Google Scholar]
  147. Wekerle H, Bradl M, Linington C, Kääb G, Kojima K. 147.  1996. The shaping of the brain-specific T lymphocyte repertoire in the thymus. Immunol. Rev. 149:231–43 [Google Scholar]
  148. Pribyl TM, Campagnoni C, Kampf K, Handley VW, Campagnoni AT. 148.  1996. The major myelin protein genes are expressed in the human thymus. J. Neurosci. Res. 45:6812–19 [Google Scholar]
  149. Derbinski J, Schulte A, Kyewski B, Klein L. 149.  2001. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat. Immunol. 2:111032–39 [Google Scholar]
  150. Nagamine K, Peterson P, Scott HS, Jun K, Minoshima S. 150.  et al. 1997. Positional cloning of the APECED gene. Nat. Genet. 17:393–98 [Google Scholar]
  151. Aaltonen J, Björses P, Perheentupa J, Horelli-Kuitunen N. 151.  et al. 1997. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. Genet. 17:4399–403 [Google Scholar]
  152. Björses P, Pelto-Huikko M, Kaukonen J, Aaltonen J, Peltonen L, Ulmanen I. 152.  1999. Localization of the APECED protein in distinct nuclear structures. Hum. Mol. Genet. 8:2259–66 [Google Scholar]
  153. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP. 153.  et al. 2002. Projection of an immunological self shadow within the thymus by the Aire protein. Science 298:55971395–1401 [Google Scholar]
  154. Villaseñor J, Besse W, Benoist C, Mathis D. 154.  2008. Ectopic expression of peripheral-tissue antigens in the thymic epithelium: probabilistic, monoallelic, misinitiated. PNAS 105:4115854–59 [Google Scholar]
  155. Tykocinski L-O, Sinemus A, Rezavandy E, Weiland Y, Baddeley D. 155.  et al. 2010. Epigenetic regulation of promiscuous gene expression in thymic medullary epithelial cells. PNAS 107:4519426–31 [Google Scholar]
  156. Sansom SN, Shikama-Dorn N, Zhanybekova S, Nusspaumer G, Macaulay IC. 156.  et al. 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 24:121918–31 [Google Scholar]
  157. Pinto S, Sommermeyer D, Michel C, Wilde S, Schendel D. 157.  et al. 2014. Misinitiation of intrathymic MART-1 transcription and biased TCR usage explain the high frequency of MART-1-specific T cells. Eur. J. Immunol. 44:92811–21 [Google Scholar]
  158. Danan-Gotthold M, Guyon C, Giraud M, Levanon EY, Abramson J. 158.  2016. Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells. Genome Biol 17:219 [Google Scholar]
  159. Derbinski J, Gäbler J, Brors B, Tierling S, Jonnakuty S. 159.  et al. 2005. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202:133–45 [Google Scholar]
  160. Brennecke P, Reyes A, Pinto S, Rattay K, Nguyen M. 160.  et al. 2015. Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells. Nat. Immunol. 16:9933–41 [Google Scholar]
  161. Meredith M, Zemmour D, Mathis D, Benoist C. 161.  2015. Aire controls gene expression in the thymic epithelium with ordered stochasticity. Nat. Immunol. 16:9942–49 [Google Scholar]
  162. Rattay K, Meyer HV, Herrmann C, Brors B, Kyewski B. 162.  2016. Evolutionary conserved gene co-expression drives generation of self-antigen diversity in medullary thymic epithelial cells. J. Autoimmun. 67:65–75 [Google Scholar]
  163. Koh AS, Kuo AJ, Park SY, Cheung P, Abramson J. 163.  et al. 2008. Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity. PNAS 105:4115878–83 [Google Scholar]
  164. Org T, Chignola F, Hetényi C, Gaetani M, Rebane A. 164.  et al. 2008. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep 9:4370–76 [Google Scholar]
  165. Org T, Rebane A, Kisand K, Laan M, Haljasorg U. 165.  et al. 2009. AIRE activated tissue specific genes have histone modifications associated with inactive chromatin. Hum. Mol. Genet. 18:244699–710 [Google Scholar]
  166. Waterfield M, Khan IS, Cortez JT, Fan U, Metzger T. 166.  et al. 2014. The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance. Nat. Immunol. 15:3258–65 [Google Scholar]
  167. Abramson J, Goldfarb Y. 167.  2016. Aire: from promiscuous molecular partnerships to promiscuous gene expression. Eur. J. Immunol. 46:122–33 [Google Scholar]
  168. Oven I, Brdicková N, Kohoutek J, Vaupotic T, Narat M, Peterlin BM. 168.  2007. AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells. Mol. Cell. Biol. 27:248815–23 [Google Scholar]
  169. Giraud M, Jmari N, Du L, Carallis F, Nieland TJF. 169.  et al. 2014. An rRNAi screen for Aire cofactors reveals a role for Hnrnpl in polymerase release and Aire-activated ectopic transcription. PNAS 111:41491–96 [Google Scholar]
  170. Yoshida H, Bansal K, Schaefer U, Chapman T, Rioja I. 170.  et al. 2015. Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells. PNAS 112:E4448–57 [Google Scholar]
  171. Giraud M, Yoshida H, Abramson J, Rahl PB, Young RA. 171.  et al. 2012. Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells. PNAS 109:2535–40 [Google Scholar]
  172. Abramson J, Giraud M, Benoist C, Mathis D. 172.  2010. Aire's partners in the molecular control of immunological tolerance. Cell 140:1123–35 [Google Scholar]
  173. Chuprin A, Avin A, Goldfarb Y, Herzig Y, Levi B. 173.  et al. 2015. The deacetylase Sirt1 is an essential regulator of Aire-mediated induction of central immunological tolerance. Nat. Immunol. 16:7737–45 [Google Scholar]
  174. Takaba H, Morishita Y, Tomofuji Y, Danks L, Nitta T. 174.  et al. 2015. Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163:4975–87 [Google Scholar]
  175. Lynch HE, Goldberg GL, Chidgey A, Van den Brink MRM, Boyd R, Sempowski GD. 175.  2009. Thymic involution and immune reconstitution. Trends Immunol 30:7366–73 [Google Scholar]
  176. Min H, Montecino-Rodriguez E, Dorshkind K. 176.  2004. Reduction in the developmental potential of intrathymic T cell progenitors with age. J. Immunol. 173:1245–50 [Google Scholar]
  177. Zediak VP, Maillard I, Bhandoola A. 177.  2007. Multiple prethymic defects underlie age-related loss of T progenitor competence. Blood 110:41161–67 [Google Scholar]
  178. Offner F, Kerre T, De Smedt M, Plum J. 178.  1999. Bone marrow CD34 cells generate fewer T cells in vitro with increasing age and following chemotherapy. Br. J. Haematol. 104:4801–8 [Google Scholar]
  179. Griffith AV, Venables T, Shi J, Farr A, van Remmen H. 179.  et al. 2015. Metabolic damage and premature thymus aging caused by stromal catalase deficiency. Cell Rep 12:71071–79 [Google Scholar]
  180. Chen L, Xiao S, Manley NR. 180.  2009. Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner. Blood 113:3567–74 [Google Scholar]
  181. Zhu X, Gui J, Dohkan J, Cheng L, Barnes PF, Su D-M. 181.  2007. Lymphohematopoietic progenitors do not have a synchronized defect with age-related thymic involution. Aging Cell 6:5663–72 [Google Scholar]
  182. Gui J, Mustachio LM, Su D-M, Craig RW. 182.  2012. Thymus size and age-related thymic involution: early programming, sexual dimorphism, progenitors and stroma. Aging Dis 3:3280–90 [Google Scholar]
  183. Gray DHD, Seach N, Ueno T, Milton MK, Liston A. 183.  et al. 2006. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 108:123777–85 [Google Scholar]
  184. Yang H, Youm Y-H, Dixit VD. 184.  2009. Inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in age-related thymic involution. J. Immunol. 183:53040–52 [Google Scholar]
  185. Aw D, Silva AB, Maddick M, von Zglinicki T, Palmer DB. 185.  2008. Architectural changes in the thymus of aging mice. Aging Cell 7:2158–67 [Google Scholar]
  186. Zook EC, Krishack PA, Zhang S, Zeleznik-Le NJ, Firulli AB. 186.  et al. 2011. Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells. Blood 118:225723–31 [Google Scholar]
  187. Youm Y-H, Horvath TL, Mangelsdorf DJ, Kliewer SA, Dixit VD. 187.  2016. Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. PNAS 113:41026–31 [Google Scholar]
  188. Olsen NJ, Olson G, Viselli SM, Gu X, Kovacs WJ. 188.  2001. Androgen receptors in thymic epithelium modulate thymus size and thymocyte development. Endocrinology 142:31278–83 [Google Scholar]
  189. Dumont-Lagacé M, St-Pierre C, Perreault C. 189.  2015. Sex hormones have pervasive effects on thymic epithelial cells. Sci. Rep. 5:12895 [Google Scholar]
  190. Tibbetts TA, DeMayo F, Rich S, Conneely OM, O'Malley BW. 190.  1999. Progesterone receptors in the thymus are required for thymic involution during pregnancy and for normal fertility. PNAS 96:2112021–26 [Google Scholar]
  191. Griffith AV, Fallahi M, Venables T, Petrie HT. 191.  2012. Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth. Aging Cell 11:1169–77 [Google Scholar]
  192. Dixit VD. 192.  2010. Thymic fatness and approaches to enhance thymopoietic fitness in aging. Curr. Opin. Immunol. 22:4521–28 [Google Scholar]
  193. Youm Y-H, Yang H, Sun Y, Smith RG, Manley NR. 193.  et al. 2009. Deficient ghrelin receptor-mediated signaling compromises thymic stromal cell microenvironment by accelerating thymic adiposity. J. Biol. Chem. 284:117068–77 [Google Scholar]
  194. Martins VC, Busch K, Juraeva D, Blum C, Ludwig C. 194.  et al. 2014. Cell competition is a tumour suppressor mechanism in the thymus. Nature 509:7501465–70 [Google Scholar]
  195. Purton JF, Monk JA, Liddicoat DR, Kyparissoudis K, Sakkal S. 195.  et al. 2004. Expression of the glucocorticoid receptor from the 1A promoter correlates with T lymphocyte sensitivity to glucocorticoid-induced cell death. J. Immunol. 173:63816–24 [Google Scholar]
  196. Gruver AL, Sempowski GD. 196.  2008. Cytokines, leptin, and stress-induced thymic atrophy. J. Leukoc. Biol. 84:4915–23 [Google Scholar]
  197. Fletcher AL, Lowen TE, Sakkal S, Reiseger JJ, Hammett MV. 197.  et al. 2009. Ablation and regeneration of tolerance-inducing medullary thymic epithelial cells after cyclosporine, cyclophosphamide, and dexamethasone treatment. J. Immunol. 183:2823–31 [Google Scholar]
  198. Williams KM, Mella H, Lucas PJ, Williams JA, Telford W, Gress RE. 198.  2009. Single cell analysis of complex thymus stromal cell populations: Rapid thymic epithelia preparation characterizes radiation injury. Clin. Transl. Sci. 2:4279–85 [Google Scholar]
  199. Erickson M, Morkowski S, Lehar S, Gillard G, Beers C. 199.  et al. 2002. Regulation of thymic epithelium by keratinocyte growth factor. Blood 100:93269–78 [Google Scholar]
  200. Min D, Panoskaltsis-Mortari A, Kuro-OM Holländer GA, Blazar BR, Weinberg KI. 200.  2007. Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 109:62529–37 [Google Scholar]
  201. Dudakov JA, Hanash AM, Jenq RR, Young LF, Ghosh A. 201.  et al. 2012. Interleukin-22 drives endogenous thymic regeneration in mice. Science 336:607791–95 [Google Scholar]
  202. Chu Y-W, Schmitz S, Choudhury B, Telford W, Kapoor V. 202.  et al. 2008. Exogenous insulin-like growth factor 1 enhances thymopoiesis predominantly through thymic epithelial cell expansion. Blood 112:72836–46 [Google Scholar]
  203. Lai L, Jin J. 203.  2009. Generation of thymic epithelial cell progenitors by mouse embryonic stem cells. Stem Cells 27:123012–20 [Google Scholar]
  204. Bredenkamp N, Ulyanchenko S, O'Neill KE, Manley NR, Vaidya HJ, Blackburn CC. 204.  2014. An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts. Nat. Cell Biol. 16:9902–8 [Google Scholar]
  205. Frank J, Pignata C, Panteleyev AA, Prowse DM, Baden H. 205.  et al. 1999. Exposing the human nude phenotype. Nature 398:6727473–74 [Google Scholar]
  206. Pantelouris EM. 206.  1968. Absence of thymus in a mouse mutant. Nature 217:5126370–71 [Google Scholar]
  207. Nehls M, Pfeifer D, Schorpp M, Hedrich H, Boehm T. 207.  1994. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 372:6501103–7 [Google Scholar]
  208. Pignata C, Fiore M, Guzzetta V, Castaldo A, Sebastio G. 208.  et al. 1996. Congenital alopecia and nail dystrophy associated with severe functional T-cell immunodeficiency in two sibs. Am. J. Med. Genet 652167–70 [Google Scholar]
  209. Gershwin ME. 209.  1977. DiGeorge syndrome: congenital thymic hypoplasia. Animal model: congenitally athymic (nude) mouse. Am. J. Pathol. 89:3809–12 [Google Scholar]
  210. Michels AW, Gottlieb PA. 210.  2010. Autoimmune polyglandular syndromes. Nat. Rev. Endocrinol. 6:5270–77 [Google Scholar]
  211. Oftedal BE, Hellesen A, Erichsen MM, Bratland E, Vardi A. 211.  et al. 2015. Dominant mutations in the autoimmune regulator AIRE are associated with common organ-specific autoimmune diseases. Immunity 42:61185–96 [Google Scholar]
  212. Kisand K, Bøe Wolff AS, Podkrajsek KT, Tserel L, Link M. 212.  et al. 2010. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med. 207:2299–308 [Google Scholar]
  213. Puel A, Döffinger R, Natividad A, Chrabieh M, Barcenas-Morales G. 213.  et al. 2010. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J. Exp. Med. 207:2291–97 [Google Scholar]
  214. Jiang W, Anderson MS, Bronson R, Mathis D, Benoist C. 214.  2005. Modifier loci condition autoimmunity provoked by Aire deficiency. J. Exp. Med. 202:6805–15 [Google Scholar]
  215. Fijolek J, Wiatr E, Demkow U, Orlowsk TM. 215.  2009. Immunological disturbances in Good's syndrome. Clin. Investig. Med. 32:4E301–6 [Google Scholar]
  216. Wolff ASB, Kärner J, Owe JF, Oftedal BEV, Gilhus NE. 216.  et al. 2014. Clinical and serologic parallels to APS-I in patients with thymomas and autoantigen transcripts in their tumors. J. Immunol. 193:83880–90 [Google Scholar]
  217. Kelleher P, Misbah SA. 217.  2003. What is Good's syndrome? Immunological abnormalities in patients with thymoma. J. Clin. Pathol. 56:112–16 [Google Scholar]
  218. Cheng MH, Fan U, Grewal N, Barnes M, Mehta A. 218.  et al. 2010. Acquired autoimmune polyglandular syndrome, thymoma, and an AIRE defect. N. Engl. J. Med. 362:8764–66 [Google Scholar]
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Thymic Epithelial Cells
Annual Review of Immunology 35, 85 (2017); https://doi.org/10.1146/annurev-immunol-051116-052320
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