Thymic epithelial cells

Annual Review of Immunology

Volumn 35, Issue , 2017, Pages 85-118

  Abramson, Jakub ^a   Anderson, Graham ^b  

^a WEIZMANN INSTITUTE OF SCIENCE   (Israel)

^b UNIVERSITY OF BIRMINGHAM   (United Kingdom)

Author keywords

Aire; Foxp3; T cell; Thymic epithelium; Thymus; Tolerance

Indexed keywords

TRANSCRIPTION FACTOR FOXP3; AUTOIMMUNE REGULATOR PROTEIN; FORKHEAD TRANSCRIPTION FACTOR; FOXP3 PROTEIN, HUMAN; TRANSCRIPTION FACTOR;

ATROPHY; AUTOIMMUNE POLYENDOCRINOPATHY CANDIDIASIS ECTODERMAL DYSTROPHY; CELL DEGENERATION; CELL DIFFERENTIATION; CELL MATURATION; CELL SELECTION; EPITHELIUM CELL; FOXN1 DEFICIENCY; GENE EXPRESSION; NONHUMAN; PIGNATA GUARINO SYNDROME; PRIORITY JOURNAL; REGENERATION; REGULATORY T LYMPHOCYTE; REVIEW; STEM CELL; T LYMPHOCYTE; THYMOMA; THYMUS; THYMUS DISEASE; ANIMAL; AUTOIMMUNITY; HUMAN; IMMUNOLOGICAL TOLERANCE; IMMUNOLOGY; METABOLISM; PATHOLOGY; PHYSIOLOGY;

ANIMALS; AUTOIMMUNITY; CELL DIFFERENTIATION; EPITHELIAL CELLS; FORKHEAD TRANSCRIPTION FACTORS; HUMANS; IMMUNE TOLERANCE; T-LYMPHOCYTES; THYMUS GLAND; TRANSCRIPTION FACTORS;

EID: 85018285755     PISSN: 07320582     EISSN: 15453278     Source Type: Book Series    
DOI: 10.1146/annurev-immunol-051116-052320     Document Type: Review

References (218)

1. Boehm T, Swann JB. 2014. Origin and evolution of adaptive immunity. Annu. Rev. Anim. Biosci. 2:259-83
2. Takahama Y. 2006. Journey through the thymus: stromal guides for T-cell development and selection. Nat. Rev. Immunol. 6(2):127-35
3. Rodewald H-R. 2008. Thymus organogenesis. Annu. Rev. Immunol. 26:355-88
4. Chaudhry MS, Velardi E, Dudakov JA, van den Brink MRM. 2016. Thymus: the next (re)generation. Immunol. Rev. 271(1):56-71
5. Rossi SW, Jenkinson WE, Anderson G, Jenkinson EJ. 2006. Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 441(7096):988-91
6. 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):992-96
7. Mayer CE, Zuklys S, Zhanybekova S, Ohigashi I, Teh H-Y, et al. 2016.Dynamic spatio-temporal contribution of singleβ5t+ cortical epithelial precursors to the thymusmedulla. Eur. J. Immunol. 46(4):846-56
8. Ohigashi I, Zuklys S, Sakata M, Mayer CE, Hamazaki Y, et al. 2015. Adult thymic medullary epithelium is maintained and regenerated by lineage-restricted cells rather than bipotent progenitors. Cell Rep. 13(7):1432-43
9. 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):1200-9
10. Baik S, Jenkinson EJ, Lane PJL, Anderson G, Jenkinson WE. 2013. Generation of both cortical and AIRE+ medullary thymic epithelial compartments from CD205+ progenitors. Eur. J. Immunol. 43(3):589-94
11. Alves NL, Takahama Y, Ohigashi I, Ribeiro AR, Baik S, et al. 2014. Serial progression of cortical and medullary thymic epithelial microenvironments. Eur. J. Immunol. 44(1):16-22
12. Gill J, Malin M, Hollander GA, Boyd R. 2002. Generation of a complete thymic microenvironment by MTS24+ thymic epithelial cells. Nat. Immunol. 3(7):635-42
13. Bennett AR, Farley A, Blair NF, Gordon J, Sharp L, Blackburn CC. 2002. Identification and characterization of thymic epithelial progenitor cells. Immunity 16(6):803-14
14. Depreter MGL, Blair NF, Gaskell TL, Nowell CS, Davern K, et al. 2008. Identification of Plet-1 as a specific marker of early thymic epithelial progenitor cells. PNAS 105(3):961-66
15. Rossi SW, Chidgey AP, Parnell SM, Jenkinson WE, Scott HS, et al. 2007. Redefining epithelial progenitor potential in the developing thymus. Eur. J. Immunol. 37(9):2411-18
16. Ucar A, Ucar O, Klug P, Matt S, Brunk F, et al. 2014. Adult thymus contains FoxN1-epithelial stem cells that are bipotent for medullary and cortical thymic epithelial lineages. Immunity 41(2):257-69
17. Wong K, Lister NL, Barsanti M, Lim JMC, Hammett MV, et al. 2014. Multilineage potential and self-renewal define an epithelial progenitor cell population in the adult thymus. Cell Rep. 8(4):1198-209
18. Ulyanchenko S, O'Neill KE, Medley T, Farley AM, Vaidya HJ, et al. 2016. Identification of a bipotent epithelial progenitor population in the adult thymus. Cell Rep. 14(12):2819-32
19. 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):763-68
20. 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):130-37
21. Rode I, Boehm T. 2012. Regenerative capacity of adult cortical thymic epithelial cells. PNAS 109(9):3463-68
22. Gray D, Abramson J, Benoist C, Mathis D. 2007. Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire. J. Exp. Med. 204(11):2521-28
23. Rossi SW, Kim M-Y, Leibbrandt A, Parnell SM, Jenkinson WE, et al. 2007.RANKsignals fromCD4+3-inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J. Exp. Med. 204(6):1267-72
24. Lkhagvasuren E, Sakata M, Ohigashi I, Takahama Y. 2013. Lymphotoxin β receptor regulates the development of CCL21-expressing subset of postnatal medullary thymic epithelial cells. J. Immunol. 190(10):5110-17
25. Hamazaki Y, Fujita H, Kobayashi T, Choi Y, Scott HS, et al. 2007. Medullary thymic epithelial cells expressing Aire represent a unique lineage derived from cells expressing claudin. Nat. Immunol. 8(3):304-11
26. 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):753-61
27. 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):857-62
28. Nowell CS, Bredenkamp N, Tetelin S, Jin X, Tischner C, et al. 2011. Foxn1 regulates lineage progression in cortical and medullary thymic epithelial cells but is dispensable for medullary sublineage divergence. PLOS Genet. 7(11):e1002348
29. Akiyama N, Takizawa N, Miyauchi M, Yanai H, Tateishi R, et al. 2016. Identification of embryonic precursor cells that differentiate into thymic epithelial cells expressing autoimmune regulator. J. Exp. Med. 213:1441-58
30. Hikosaka Y, Nitta T, Ohigashi I, Yano K, Ishimaru N, et al. 2008. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 29(3):438-50
31. Akiyama T, Shimo Y, Yanai H, Qin J, Ohshima D, et al. 2008. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29(3):423-37
32. Mouri Y, Yano M, Shinzawa M, Shimo Y, Hirota F, et al. 2011. Lymphotoxin signal promotes thymic organogenesis by eliciting rank expression in the embryonic thymic stroma. J. Immunol. 186(9):5047-57
33. Onder L, Nindl V, Scandella E, Chai Q, Cheng H-W, et al. 2015. AlternativeNF-κB signaling regulates mTEC differentiation from podoplanin-expressing presursors in the cortico-medullary junction. Eur. J. Immunol. 45(8):2218-31
34. Manley NR, Condie BG. 2010. Transcriptional regulation of thymus organogenesis and thymic epithelial cell differentiation. Prog. Mol. Biol. Transl. Sci. 92(10):103-20
35. Goldfarb Y, Kadouri N, Levi B, Sela A, Herzig Y, et al. 2016. HDAC3 is a master regulator of mTEC development. Cell Rep. 15(3):651-65
36. Nehls M, Kyewski B, Messerle M, Waldschutz R, Schuddekopf K, et al. 1996. Two genetically separable steps in the differentiation of thymic epithelium. Science 272(5263):886-89
37. Cheng L, Guo J, Sun L, Fu J, Barnes PF, et al. 2010. Postnatal tissue-specific disruption of transcription factor FoxN1 triggers acute thymic atrophy. J. Biol. Chem. 285(8):5836-47
38. Rode I, Martins VC, Kublbeck G, Maltry N, Tessmer C, Rodewald H-R. 2015. Foxn1 protein expression in the developing, aging, and regenerating thymus. J. Immunol. 195(12):5678-87
39. Zuklys S, Handel A, Zhanybekova S, Govani F, Keller M, et al. 2016. Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells. Nat. Immunol. 17:1206-15
40. Bleul CC, Boehm T. 2005. BMP signaling is required for normal thymus development. J. Immunol. 175(8):5213-21
41. Gordon J, Patel SR, Mishina Y, Manley NR. 2010. Evidence for an early role for BMP4 signaling in thymus and parathyroid morphogenesis. Dev. Biol. 339(1):141-54
42. Balciunaite G, Keller MP, Balciunaite E, Piali L, Zuklys S, et al. 2002. Wnt glycoproteins regulate the expression of FoxN1, the gene defective in nude mice. Nat. Immunol. 3(11):1102-8
43. Heinonen KM, Vanegas JR, Brochu S, Shan J, Vainio SJ, Perreault C. 2011. Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors. Blood 118(19):5163-73
44. LiangC-C, You L-R, Yen JJY, Liao N-S, Yang-Yen H-F, Chen C-M. 2013. Thymic epithelialβ-catenin is required for adult thymic homeostasis and function. Immunol. Cell Biol. 91(8):511-23
45. Osada M, Jardine L, Misir R, Andl T, Millar SE, Pezzano M. 2010. DKK1 mediated inhibition of Wnt signaling in postnatal mice leads to loss of TEC progenitors and thymic degeneration. PLOS ONE 5(2):e9062
46. Zuklys S, Gill J, KellerMP, Hauri-Hohl M, Zhanybekova S, et al. 2009. Stabilized beta-catenin in thymic epithelial cells blocks thymus development and function. J. Immunol. 182(5):2997-3007
47. Wang H-X, Shin J, Wang S, Gorentla B, Lin X, 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(2):e1002370
48. Wang H-X, Cheng JS, Chu S, Qiu Y-R, Zhong X-P. 2016. mTORC2 in thymic epithelial cells controls thymopoiesis and T cell development. J. Immunol. 197(1):141-50
49. Candi E, Rufini A, Terrinoni A, Giamboi-Miraglia A, Lena AM, et al. 2007. Np63 regulates thymic development through enhanced expression of FgfR2 and Jag2. PNAS 104(29):11999-2004
50. Liu B, Liu Y-F, Du Y-R, Mardaryev AN, Yang W, et al. 2013. Cbx4 regulates the proliferation of thymic epithelial cells and thymus function. Development 140(4):780-88
51. Papadopoulou AS, Dooley J, Linterman MA, Pierson W, Ucar O, et al. 2011. The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution viamiR-29a mediated suppression of the IFN-areceptor. Nat. Immunol. 13(2):181-87
52. Zuklys S, Mayer CE, Zhanybekova S, Stefanski HE, Nusspaumer G, et al. 2012. microRNAs control the maintenance of thymic epithelia and their competence for T lineage commitment and thymocyte selection. J. Immunol. 189(8):3894-904
53. 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):1954-61
54. Dooley J, Erickson M, Larochelle WJ, Gillard GO, Farr AG. 2007. FgfR2IIIb signaling regulates thymic epithelial differentiation. Dev. Dyn. 236(12):3459-71
55. Saldana JI, Solanki A, Lau C-I, Sahni H, Ross S, et al. 2016. Sonic Hedgehog regulates thymic epithelial cell differentiation. J. Autoimmun. 68:86-97
56. Parent AV, Russ HA, Khan IS, LaFlam TN, Metzger TC, et al. 2013. Generation of functional thymic epithelium from human embryonic stem cells that supports host T cell development. Cell Stem Cell. 13(2):219-29
57. Sun X, Xu J, Lu H, Liu W, Miao Z, 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(2):230-36
58. Su M, Hu R, Jin J, Yan Y, Song Y, et al. 2015. Efficient in vitro generation of functional thymic epithelial progenitors from human embryonic stem cells. Sci. Rep. 5:9882
59. 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):4801-9
60. Masuda K, Germeraad WTV, Satoh R, Itoi M, Ikawa T, et al. 2009. Notch activation in thymic epithelial cells induces development of thymic microenvironments. Mol. Immunol. 46(8-9):1756-67
61. BoehmT, 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 LTβR. J. Exp. Med. 198(5):757-69
62. Satoh R, Kakugawa K, Yasuda T, Yoshida H, Sibilia M, et al. 2016. Requirement of Stat3 signaling in the postnatal development of thymic medullary epithelial cells. PLOS Genet. 12(1):e1005776
63. Metzger TC, Khan IS, Gardner JM, Mouchess ML, Johannes KP, et al. 2013. Lineage tracing and cell ablation identify a post-Aire-expressing thymic epithelial cell population. Cell Rep. 5(1):166-79
64. Yano M, Kuroda N, Han H, Meguro-Horike M, Nishikawa Y, 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(12):2827-38
65. Kanariou M, Huby R, Ladyman H, Colic M, Sivolapenko G, et al. 1989. Immunosuppression with cyclosporin A alters the thymic microenvironment. Clin. Exp. Immunol. 78(2):263-70
66. Shores EW, Van Ewijk W, Singer A. 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(7):1657-61
67. Hollander GA, Wang B, Nichogiannopoulou A, Platenburg PP, van Ewijk W, et al. 1995. Developmental control point in induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature 373(6512):350-53
68. Palmer DB, Viney JL, Ritter MA, Hayday AC, Owen MJ. 1993. Expression of the αβ T-cell receptor is necessary for the generation of the thymic medulla. Dev. Immunol. 3(3):175-79
69. Velardi E, Tsai JJ, Holland AM, Wertheimer T, Yu VWC, et al. 2014. Sex steroid blockade enhances thymopoiesis by modulating notch signaling. J. Exp. Med. 211(12):2341-49
70. Fiorini E, Ferrero I, Merck E, Favre S, Pierres M, et al. 2008. Cutting edge: Thymic crosstalk regulates delta-like 4 expression on cortical epithelial cells. J. Immunol. 181(12):8199-203
71. Alves NL, Huntington ND, Mention J-J, 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):5949-53
72. Anderson G, Takahama Y. 2012. Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol. 33(6):256-63
73. Chin RK, Lo JC, Kim O, Blink SE, Christiansen PA, et al. 2003. Lymphotoxin pathway directs thymic Aire expression. Nat. Immunol. 4:1121-27
74. Venanzi ES, Gray DHD, Benoist C, Mathis D. 2007. Lymphotoxin pathway and Aire influences on thymic medullary epithelial cells are unconnected. J. Immunol. 179(9):5693-700
75. Martins VC, Boehm T, Bleul CC. 2008. LTβR signaling does not regulate Aire-dependent transcripts in medullary thymic epithelial cells. J. Immunol. 181(1):400-7
76. White AJ, Nakamura K, Jenkinson WE, Saini M, Sinclair C, et al. 2010. Lymphotoxin signals from positively selected thymocytes regulate the terminal differentiation of medullary thymic epithelial cells. J. Immunol. 185(8):4769-76
77. McCarthy NI, Cowan JE, Nakamura K, Bacon A, Baik S, et al. 2015. Osteoprotegerin-mediated homeostasis of Rank+ thymic epithelial cells does not limit Foxp3+ regulatory T cell development. J. Immunol. 195(6):2675-82
78. Desanti GE, Cowan JE, Baik S, Parnell SM, White AJ, 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(12):5519-26
79. Irla M, Hugues S, Gill J, Nitta T, Hikosaka Y, et al. 2008. Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity. Immunity. 29(3):451-63
80. Roberts NA, White AJ, Jenkinson WE, Turchinovich G, Nakamura K, et al. 2012. Rank signaling links the development of invariant γδ T cell progenitors and Aire+ medullary epithelium. Immunity 36(3):427-37
81. White AJ, Jenkinson WE, Cowan JE, Parnell SM, Bacon A, et al. 2014. An essential role for medullary thymic epithelial cells during the intrathymic development of invariant NKT cells. J. Immunol. 192(6):2659-66
82. Guerau-de-Arellano M, Martinic M, Benoist C, Mathis D. 2009. Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity. J. Exp. Med. 206(6):1245-52
83. Zhang SL, Bhandoola A. 2014. Trafficking to the thymus. Curr. Top. Microbiol. Immunol. 373:87-111
84. Gossens K, Naus S, Corbel SY, Lin S, Rossi FMV, et al. 2009. Thymic progenitor homing and lymphocyte homeostasis are linked via S1P-controlled expression of thymic P-selectin/CCL25. J. Exp. Med. 206(4):761-78
85. Bleul CC, Boehm T. 2000. Chemokines define distinct microenvironments in the developing thymus. Eur. J. Immunol. 30(12):3371-79
86. Jenkinson WE, Rossi SW, Parnell SM, Agace WW, Takahama Y, et al. 2007. Chemokine receptor expression defines heterogeneity in the earliest thymic migrants. Eur. J. Immunol. 37(8):2090-96
87. 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):4521-27
88. Ueno T, Hara K, Willis MS, Malin MA, Hopken UE, et al. 2002. Role forCCR7ligands in the emigration of newly generated T lymphocytes from the neonatal thymus. Immunity 16(2):205-18
89. Lucas B, White AJ, Ulvmar MH, Nibbs RJB, Sitnik KM, 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(2):574-83
90. Griffith AV, Fallahi M, Nakase H, Gosink M, Young B, Petrie HT. 2009. Spatial mapping of thymic stromal microenvironments reveals unique features influencing T lymphoid differentiation. Immunity 31(6):999-1009
91. Buono M, Facchini R, Matsuoka S, Thongjuea S, Waithe D, et al. 2016. A dynamic niche provides Kit ligand in a stage-specific manner to the earliest thymocyte progenitors. Nat. Cell Biol. 18(2):157-67
92. Alves NL, Richard-Le Goff O, Huntington ND, Sousa AP, Ribeiro VSG, et al. 2009. Characterization of the thymic IL-7 niche in vivo. PNAS 106(5):1512-17
93. Hozumi K, Mailhos C, Negishi N, Hirano K, Yahata T, et al. 2008. Delta-like 4 is indispensable in thymic environment specific for T cell development. J. Exp. Med. 205(11):2507-13
94. Koch U, Fiorini E, Benedito R, Besseyrias V, Schuster-Gossler K, et al. 2008. Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. J. Exp. Med. 205(11):2515-23
95. Ferrero I, Koch U, Claudinot S, Favre S, Radtke F, et al. 2013. DL4-mediated Notch signaling is required for the development of fetal αβand γδT cells. Eur. J. Immunol. 43(11):2845-53
96. 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):396-400
97. Jenkinson WE, Nakamura K, White AJ, Jenkinson EJ, Anderson G. 2012. NormalTcell selection occurs in CD205-deficient thymic microenvironments. PLOS ONE 7(12):e53416
98. Honey K, Nakagawa T, Peters C, Rudensky A. 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(10):1349-58
99. Gommeaux J, Gregoire C, Nguessan P, Richelme M, Malissen M, et al. 2009. Thymus-specific serine protease regulates positive selection of a subset of CD4+ thymocytes. Eur. J. Immunol. 39(4):956-64
100. Murata S, Sasaki K, Kishimoto T, Niwa S-I, Hayashi H, et al. 2007. Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 316(5829):1349-53
101. Nitta T, Murata S, Sasaki K, Fujii H, Ripen AM, et al. 2010. Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. Immunity 32(1):29-40
102. Takada K, Van Laethem F, Xing Y, Akane K, Suzuki H, et al. 2015. TCR affinity for thymoproteasomedependent positively selecting peptides conditions antigen responsiveness inCD8+ Tcells. Nat. Immunol. 16(10):1069-76
103. Sasaki K, Takada K, Ohte Y, Kondo H, Sorimachi H, et al. 2015. Thymoproteasomes produce unique peptide motifs for positive selection of CD8+ T cells. Nat. Commun. 6:7484
104. Wekerle H, Ketelsen UP. 1980. Thymic nurse cells-Ia-bearing epithelium involved in T-lymphocyte differentiation? Nature 283(5745):402-4
105. Nakagawa Y, Ohigashi I, Nitta T, Sakata M, Tanaka K, et al. 2012. Thymic nurse cells providemicroenvironment for secondaryTcell receptorarearrangement in cortical thymocytes. PNAS 109(50):20572-77
106. Stritesky GL, Xing Y, Erickson JR, Kalekar LA, Wang X, et al. 2013. Murine thymic selection quantified using a unique method to capture deleted T cells. PNAS 110(12):4679-84
107. McCaughtry TM, Baldwin TA, Wilken MS, Hogquist KA. 2008. Clonal deletion of thymocytes can occur in the cortex with no involvement of the medulla. J. Exp. Med. 205(11):2575-84
108. Xing Y, Wang X, Jameson SC, Hogquist KA. 2016. Late stages of T cell maturation in the thymus involve NF-κB and tonic type I interferon signaling. Nat. Immunol. 17(5):565-73
109. Klein L, Kyewski B, Allen PM, Hogquist KA. 2014. Positive and negative selection of theTcell repertoire: what thymocytes see (and don't see). Nat. Rev. Immunol. 14(6):377-91
110. Kyewski B, Klein L. 2006. A central role for central tolerance. Annu. Rev. Immunol. 24:571-606
111. Taniguchi RT, DeVoss JJ, Moon JJ, Sidney J, Sette A, et al. 2012. Detection of an autoreactive Tcell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection. PNAS 109(20):7847-52
112. Lei Y, Ripen AM, Ishimaru N, Ohigashi I, Nagasawa T, 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(2):383-94
113. Mouri Y, Nishijima H, Kawano H, Hirota F, Sakaguchi N, 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(9):4356-67
114. Baba T, Nakamoto Y, Mukaida N. 2009. Crucial contribution of thymic Sirpa+ conventional dendritic cells to central tolerance against blood-borne antigens in a CCR2-dependent manner. J. Immunol. 183(5):3053-63
115. Hadeiba H, Lahl K, Edalati A, Oderup C, Habtezion A, et al. 2012. Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. Immunity 36(3):438-50
116. Davis MM. 2015. Not-so-negative selection. Immunity 43(5):833-35
117. Malhotra D, Linehan JL, Dileepan T, Lee YJ, Purtha WE, et al. 2016. Tolerance is established in polyclonal CD4+ T cells by distinct mechanisms, according to self-peptide expression patterns. Nat. Immunol. 17(2):187-95
118. Legoux FP, Lim J-B, Cauley AW, Dikiy S, Ertelt J, et al. 2015. CD4+ Tcell tolerance to tissue-restricted self antigens is mediated by antigen-specific regulatory T cells rather than deletion. Immunity 43(5):896-908
119. Aschenbrenner K, D'Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, 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(4):351-58
120. Wirnsberger G, Hinterberger M, Klein L. 2011. Regulatory T-cell differentiation versus clonal deletion of autoreactive thymocytes. Immunol. Cell Biol. 89(1):45-53
121. Coquet JM, Ribot JC, Babala N, Middendorp S, van der Horst G, 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(4):715-28
122. Cowan JE, Parnell SM, Nakamura K, Caamano JH, Lane PJL, et al. 2013. The thymicmedulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development. J. Exp. Med. 210(4):675-81
123. Tai X, Erman B, Alag A, Mu J, Kimura M, et al. 2013. Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity 38(6):1116-28
124. Lio C-WJ, Hsieh C-S. 2008. A two-step process for thymic regulatory T cell development. Immunity 28(1):100-11
125. Mahmud SA, Manlove LS, Schmitz HM, Xing Y, Wang Y, et al. 2014. Costimulation via the tumornecrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat. Immunol. 15(5):473-81
126. Hale JS, Fink PJ. 2009. Back to the thymus: PeripheralTcells come home. Immunol. Cell Biol. 87(1):58-64
127. Kirberg J, Bosco N, Deloulme J-C, Ceredig R, Agenes F. 2008. Peripheral T lymphocytes recirculating back into the thymus can mediate thymocyte positive selection. J. Immunol. 181(2):1207-14
128. McCaughtry TM, Wilken MS, Hogquist KA. 2007. Thymic emigration revisited. J. Exp. Med. 204(11):2513-20
129. Cowan JE, McCarthy NI, Anderson G. 2016. CCR7 controls thymus recirculation, but not production and emigration, of Foxp3+ T cells. Cell Rep. 14(5):1041-48
130. Hauri-Hohl M, Zuklys S, Hollander GA, Ziegler SF. 2014. A regulatory role for TGF-β signaling in the establishment and function of the thymic medulla. Nat. Immunol. 15(6):554-61
131. Akiyama N, Shinzawa M, Miyauchi M, Yanai H, Tateishi R, et al. 2014. Limitation of immune toleranceinducing thymic epithelial cell development by Spi-B-mediated negative feedback regulation. J. Exp. Med. 211(12):2425-38
132. Thiault N, Darrigues J, Adoue V, Gros M, Binet B, et al. 2015. Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors. Nat. Immunol. 16(6):628-34
133. Weist BM, Kurd N, Boussier J, Chan SW, Robey EA. 2015. Thymic regulatory T cell niche size is dictated by limiting IL-2 from antigen-bearing dendritic cells and feedback competition. Nat. Immunol. 16(6):635-41
134. Stritesky GL, Jameson SC, Hogquist KA. 2012. Selection of self-reactive T cells in the thymus. Annu. Rev. Immunol. 30:95-114
135. Bendelac A. 1995. Positive selection of mouse NK1+ T cells by CD1-expressing cortical thymocytes. J. Exp. Med. 182(6):2091-96
136. Nitta T, Muro R, Shimizu Y, Nitta S, Oda H, et al. 2015. The thymic cortical epithelium determines the TCR repertoire of IL-17-producing γδT cells. EMBO Rep. 16(5):638-53
137. Kappler JW, Roehm N, Marrack P. 1987. T cell tolerance by clonal elimination in the thymus. Cell 49(2):273-80
138. Kisielow P, BluthmannH, Staerz UD, SteinmetzM, von BoehmerH. 1988. Tolerance inT-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature 333(6175):742-46
139. Miller JF, Morahan G, Allison J. 1989. Extrathymic acquisition of tolerance by T lymphocytes. Cold Spring Harb. Symp. Quant. Biol. 54:807-13
140. Linsk R, Gottesman M, Pernis B. 1989. Are tissues a patch quilt of ectopic gene expression? Science 246(4927):261
141. Ohki H, Martin C, Corbel C, Coltey M, Le DouarinNM. 1987. Tolerance induced by thymic epithelial grafts in birds. Science 237(4818):1032-35
142. Kirchner T, Tzartos S, Hoppe F, Schalke B, Wekerle H, Muller-Hermelink HK. 1988. Pathogenesis of myasthenia gravis: acetylcholine receptor-related antigenic determinants in tumor-free thymuses and thymic epithelial tumors. Am. J. Pathol. 130(2):268-80
143. Jolicoeur C, Hanahan D, Smith KM. 1994. T-cell tolerance toward a transgenic β-cell antigen and transcription of endogenous pancreatic genes in thymus. PNAS 91(14):6707-11
144. Sospedra M, Ferrer-Francesch X, Dominguez O, Juan M, Foz-Sala M, Pujol-Borrell R. 1998. Transcription of a broad range of self-antigens in human thymus suggests a role for central mechanisms in tolerance toward peripheral antigens. J. Immunol. 161(11):5918-29
145. 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):1355-65
146. Klein L, Klein T, Ruther U, Kyewski B. 1998. CD4 T cell tolerance to human C-reactive protein, an inducible serum protein, is mediated by medullary thymic epithelium. J. Exp. Med. 188(1):5-16
147. Wekerle H, Bradl M, Linington C, Kaab G, Kojima K. 1996. The shaping of the brain-specific T lymphocyte repertoire in the thymus. Immunol. Rev. 149:231-43
148. Pribyl TM, Campagnoni C, Kampf K, Handley VW, Campagnoni AT. 1996. The major myelin protein genes are expressed in the human thymus. J. Neurosci. Res. 45(6):812-19
149. 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):1032-39
150. Nagamine K, Peterson P, ScottHS, Jun K, Minoshima S, et al. 1997. Positional cloning of the APECED gene. Nat. Genet. 17:393-98
151. Aaltonen J, Bjorses P, Perheentupa J, Horelli-Kuitunen N, et al. 1997. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. Genet. 17(4):399-403
152. Bjorses P, Pelto-Huikko M, Kaukonen J, Aaltonen J, Peltonen L, Ulmanen I. 1999. Localization of the APECED protein in distinct nuclear structures. Hum. Mol. Genet. 8(2):259-66
153. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, et al. 2002. Projection of an immunological self shadow within the thymus by the Aire protein. Science 298(5597):1395-1401
154. Villasenor J, Besse W, Benoist C, Mathis D. 2008. Ectopic expression of peripheral-tissue antigens in the thymic epithelium: probabilistic, monoallelic, misinitiated. PNAS 105(41):15854-59
155. Tykocinski L-O, Sinemus A, Rezavandy E, Weiland Y, Baddeley D, et al. 2010. Epigenetic regulation of promiscuous gene expression in thymic medullary epithelial cells. PNAS 107(45):19426-31
156. Sansom SN, Shikama-Dorn N, Zhanybekova S, Nusspaumer G, Macaulay IC, 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(12):1918-31
157. Pinto S, Sommermeyer D, Michel C, Wilde S, Schendel D, 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(9):2811-21
158. Danan-Gotthold M, Guyon C, Giraud M, Levanon EY, Abramson J. 2016. Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells. Genome Biol. 17:219
159. Derbinski J, Gabler J, Brors B, Tierling S, Jonnakuty S, et al. 2005. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202(1):33-45
160. Brennecke P, Reyes A, Pinto S, Rattay K, Nguyen M, et al. 2015. Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells. Nat. Immunol. 16(9):933-41
161. Meredith M, Zemmour D, Mathis D, Benoist C. 2015. Aire controls gene expression in the thymic epithelium with ordered stochasticity. Nat. Immunol. 16(9):942-49
162. Rattay K, Meyer HV, Herrmann C, Brors B, Kyewski B. 2016. Evolutionary conserved gene coexpression drives generation of self-antigen diversity in medullary thymic epithelial cells. J. Autoimmun. 67:65-75
163. Koh AS, Kuo AJ, Park SY, Cheung P, Abramson J, et al. 2008. Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity. PNAS 105(41):15878-83
164. Org T, Chignola F, Hetenyi C, Gaetani M, Rebane A, et al. 2008. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep. 9(4):370-76
165. Org T, Rebane A, Kisand K, Laan M, Haljasorg U, et al. 2009. AIRE activated tissue specific genes have histone modifications associated with inactive chromatin. Hum. Mol. Genet. 18(24):4699-710
166. Waterfield M, Khan IS, Cortez JT, Fan U, Metzger T, et al. 2014. The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance. Nat. Immunol. 15(3):258-65
167. Abramson J, Goldfarb Y. 2016. Aire: from promiscuous molecular partnerships to promiscuous gene expression. Eur. J. Immunol. 46(1):22-33
168. Oven I, Brdickova N, Kohoutek J, Vaupotic T, Narat M, Peterlin BM. 2007. AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells. Mol. Cell. Biol. 27(24):8815-23
169. Giraud M, Jmari N, Du L, Carallis F, Nieland TJF, et al. 2014. An rRNAi screen for Aire cofactors reveals a role for Hnrnpl in polymerase release and Aire-activated ectopic transcription. PNAS 111(4):1491-96
170. Yoshida H, Bansal K, Schaefer U, Chapman T, Rioja I, 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
171. Giraud M, Yoshida H, Abramson J, Rahl PB, Young RA, et al. 2012. Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells. PNAS 109(2):535-40
172. Abramson J, Giraud M, Benoist C, Mathis D. 2010. Aire's partners in the molecular control of immunological tolerance. Cell 140(1):123-35
173. Chuprin A, Avin A, Goldfarb Y, Herzig Y, Levi B, et al. 2015. The deacetylase Sirt1 is an essential regulator of Aire-mediated induction of central immunological tolerance. Nat. Immunol. 16(7):737-45
174. Takaba H, Morishita Y, Tomofuji Y, Danks L, Nitta T, et al. 2015. Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163(4):975-87
175. Lynch HE, Goldberg GL, Chidgey A, Van den Brink MRM, Boyd R, Sempowski GD. 2009. Thymic involution and immune reconstitution. Trends Immunol. 30(7):366-73
176. Min H, Montecino-Rodriguez E, Dorshkind K. 2004. Reduction in the developmental potential of intrathymic T cell progenitors with age. J. Immunol. 173(1):245-50
177. Zediak VP, Maillard I, Bhandoola A. 2007. Multiple prethymic defects underlie age-related loss of T progenitor competence. Blood 110(4):1161-67
178. Offner F, Kerre T, De SmedtM, Plum J. 1999. Bone marrow CD34 cells generate fewer T cells in vitro with increasing age and following chemotherapy. Br. J. Haematol. 104(4):801-8
179. Griffith AV, Venables T, Shi J, Farr A, van Remmen H, et al. 2015. Metabolic damage and premature thymus aging caused by stromal catalase deficiency. Cell Rep. 12(7):1071-79
180. Chen L, Xiao S, Manley NR. 2009. Foxn1 is required tomaintain the postnatal thymic microenvironment in a dosage-sensitive manner. Blood 113(3):567-74
181. Zhu X, Gui J, Dohkan J, Cheng L, Barnes PF, Su D-M. 2007. Lymphohematopoietic progenitors do not have a synchronized defect with age-related thymic involution. Aging Cell. 6(5):663-72
182. Gui J, Mustachio LM, Su D-M, Craig RW. 2012. Thymus size and age-related thymic involution: early programming, sexual dimorphism, progenitors and stroma. Aging Dis. 3(3):280-90
183. Gray DHD, Seach N, Ueno T, Milton MK, Liston A, et al. 2006. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 108(12):3777-85
184. Yang H, Youm Y-H, Dixit VD. 2009. Inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in age-related thymic involution. J. Immunol. 183(5):3040-52
185. Aw D, Silva AB, Maddick M, von Zglinicki T, Palmer DB. 2008. Architectural changes in the thymus of aging mice. Aging Cell. 7(2):158-67
186. Zook EC, Krishack PA, Zhang S, Zeleznik-Le NJ, Firulli AB, et al. 2011. Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells. Blood 118(22):5723-31
187. Youm Y-H, Horvath TL, Mangelsdorf DJ, Kliewer SA, Dixit VD. 2016. Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. PNAS 113(4):1026-31
188. 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):1278-83
189. Dumont-Lagace M, St-Pierre C, Perreault C. 2015. Sex hormones have pervasive effects on thymic epithelial cells. Sci. Rep. 5:12895
190. Tibbetts TA, DeMayo F, Rich S, Conneely OM, O'Malley BW. 1999. Progesterone receptors in the thymus are required for thymic involution during pregnancy and for normal fertility.PNAS 96(21):12021-26
191. Griffith AV, Fallahi M, Venables T, Petrie HT. 2012. Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth. Aging Cell 11(1):169-77
192. Dixit VD. 2010. Thymic fatness and approaches to enhance thymopoietic fitness in aging. Curr. Opin. Immunol. 22(4):521-28
193. Youm Y-H, Yang H, Sun Y, Smith RG, Manley NR, et al. 2009. Deficient ghrelin receptor-mediated signaling compromises thymic stromal cell microenvironment by accelerating thymic adiposity. J. Biol. Chem. 284(11):7068-77
194. Martins VC, BuschK, Juraeva D, Blum C, Ludwig C, et al. 2014. Cell competition is a tumour suppressor mechanism in the thymus. Nature 509(7501):465-70
195. Purton JF, Monk JA, Liddicoat DR, Kyparissoudis K, Sakkal S, 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(6):3816-24
196. Gruver AL, Sempowski GD. 2008. Cytokines, leptin, and stress-induced thymic atrophy. J. Leukoc. Biol. 84(4):915-23
197. Fletcher AL, Lowen TE, Sakkal S, Reiseger JJ, Hammett MV, et al. 2009. Ablation and regeneration of tolerance-inducing medullary thymic epithelial cells after cyclosporine, cyclophosphamide, and dexamethasone treatment. J. Immunol. 183(2):823-31
198. Williams KM, Mella H, Lucas PJ, Williams JA, Telford W, Gress RE. 2009. Single cell analysis of complex thymus stromal cell populations: Rapid thymic epithelia preparation characterizes radiation injury. Clin. Transl. Sci. 2(4):279-85
199. Erickson M, Morkowski S, Lehar S, Gillard G, Beers C, et al. 2002. Regulation of thymic epithelium by keratinocyte growth factor. Blood 100(9):3269-78
200. Min D, Panoskaltsis-Mortari A, Kuro-OM Hollander GA, Blazar BR, Weinberg KI. 2007. Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 109(6):2529-37
201. Dudakov JA, Hanash AM, Jenq RR, Young LF, Ghosh A, et al. 2012. Interleukin-22 drives endogenous thymic regeneration in mice. Science 336(6077):91-95
202. Chu Y-W, Schmitz S, Choudhury B, Telford W, Kapoor V, et al. 2008. Exogenous insulin-like growth factor 1 enhances thymopoiesis predominantly through thymic epithelial cell expansion. Blood 112(7):2836-46
203. Lai L, Jin J. 2009. Generation of thymic epithelial cell progenitors by mouse embryonic stem cells. Stem Cells. 27(12):3012-20
204. Bredenkamp N, Ulyanchenko S, O'Neill KE, Manley NR, Vaidya HJ, Blackburn CC. 2014. An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts. Nat. Cell Biol. 16(9):902-8
205. Frank J, Pignata C, Panteleyev AA, Prowse DM, Baden H, et al. 1999. Exposing the human nude phenotype. Nature 398(6727):473-74
206. Pantelouris EM. 1968. Absence of thymus in a mouse mutant. Nature 217(5126):370-71
207. NehlsM, Pfeifer D, SchorppM, Hedrich H, Boehm T. 1994. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 372(6501):103-7
208. Pignata C, Fiore M, Guzzetta V, Castaldo A, Sebastio G, et al. 1996. Congenital alopecia and nail dystrophy associated with severe functional T-cell immunodeficiency in two sibs. Am. J. Med. Genet. 65(2):167-70
209. Gershwin ME. 1977. DiGeorge syndrome: congenital thymic hypoplasia. Animal model: congenitally athymic (nude) mouse. Am. J. Pathol. 89(3):809-12
210. Michels AW, Gottlieb PA. 2010. Autoimmune polyglandular syndromes. Nat. Rev. Endocrinol. 6(5):270-77
211. Oftedal BE, Hellesen A, Erichsen MM, Bratland E, Vardi A, et al. 2015. Dominant mutations in the autoimmune regulator AIRE are associated with common organ-specific autoimmune diseases. Immunity 42(6):1185-96
212. Kisand K, Boe Wolff AS, Podkrajsek KT, Tserel L, Link M, et al. 2010. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med. 207(2):299-308
213. Puel A, Doffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, et al. 2010. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronicmucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J. Exp. Med. 207(2):291-97
214. JiangW, Anderson MS, Bronson R, Mathis D, Benoist C. 2005. Modifier loci condition autoimmunity provoked by Aire deficiency. J. Exp. Med. 202(6):805-15
215. Fijolek J, Wiatr E, Demkow U, Orlowsk TM. 2009. Immunological disturbances in Good's syndrome. Clin. Investig. Med. 32(4):E301-6
216. Wolff ASB, Karner J, Owe JF, Oftedal BEV, Gilhus NE, et al. 2014. Clinical and serologic parallels to APS-I in patientswith thymomas and autoantigen transcripts in their tumors. J. Immunol. 193(8):3880-90
217. Kelleher P, Misbah SA. 2003. What is Good's syndrome? Immunological abnormalities in patients with thymoma. J. Clin. Pathol. 56(1):12-16
218. Cheng MH, Fan U, Grewal N, Barnes M, Mehta A, et al. 2010. Acquired autoimmune polyglandular syndrome, thymoma, and an AIRE defect. N. Engl. J. Med. 362(8):764-66