TNF receptor family signaling in the development and functions of medullary thymic epithelial cells

Frontiers in Immunology

Volumn 3, Issue SEP, 2012, Pages

  Akiyama, Taishin ^a   Shinzawa, Miho ^a   Akiyama, Nobuko ^a  

^a UNIVERSITY OF TOKYO   (Japan)

Author keywords

Autoimmune disease; Medullary thymic epithelial cells; NF B; Self tolerance; Signal transduction; TNF receptor family

Indexed keywords

EID: 84872172303     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2012.00278     Document Type: Short Survey

References (117)

1. Aggarwal, B. (2003). Signalling pathways of the TNF superfamily: a double-edged sword. Nat. Rev. Immunol. 3, 745-756.
2. Aggarwal, B. B., Gupta, S. C., and Kim, J. H. (2012). Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood 119, 651-665.
3. Akiyama, T., Maeda, S., Yamane, S., Ogino, K., Kasai, M., Kajiura, R, Matsumoto, M., and Inoue, J. (2005). Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 308, 248-251.
4. Akiyama, T., Shimo, Y., Yanai, H., Qin, J., Ohshima, D., Maruyama, Y., Asaumi, Y., Kitazawa, J., Takayanagi, H., Penninger, J., Matsumoto, M., Nitta, T., Takahama, Y., and Inoue, J. (2008). The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenviron-ment and self-tolerance. Immunity 29, 423-437.
5. Anderson, D. M., Maraskovsky, E., Billingsley, W. L., Dougall, W. C., Tometsko, M. E., Roux, E. R., Teepe, M. C., DuBose, R. F., Cosman, D., and Galibert, L. (1997). A homo-logue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390, 175-179.
6. Anderson, G., Lane, P. J., and Jenkinson, E. J. (2007). Generating intrathymic microenvironments to establish T-cell tolerance. Nat. Rev. Immunol. 7, 954-963.
7. Anderson, G., and Takahama, Y (2012). Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol. 33, 256-263.
8. Anderson, M., Venanzi, E., Klein, L., Chen, Z., Berzins, S., Turley, S., von Boehmer, H., Bronson, R., Dierich, A., Benoist, C., and Mathis, D. (2002). Projection of an immuno-logical self shadow within the thy-mus by the aire protein. Science 298, 1395-1401.
9. Barbee, S. D., Woodward, M. J., Turchinovich, G., Mention, J. J., Lewis, J. M., Boyden, L. M., Lifton, R. P., Tigelaar, R., and Hayday, A. C. (2011). Skint-1 is a highly specific, unique selecting component for epidermal T cells. Proc. Natl. Acad. Sci. U.S.A. 108, 3330-3335.
10. Bensinger, S., Bandeira, A., Jordan, M., Caton, A., and Laufer, T. (2001). Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4(+)25(+) immunoregulatory T cells. J. Exp. Med. 194, 427-438.
11. Bishop, G. A., Moore, C. R., Xie, P., Stunz, L. L., and Kraus, Z. J. (2007). TRAF proteins in CD40 signaling. Adv. Exp. Med. Biol. 597, 131-151.
12. Blackburn, C. C., and Manley, N. R. (2004). Developing a new paradigm for thymus organogenesis. Nat. Rev. Immunol. 4, 278-289.
13. Bleul, C. C., Corbeaux, T., Reuter, A., Fisch, P., Mönting, J. S., and Boehm, T. (2006). Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 441, 992-996.
14. Boehm, T., Scheu, S., Pfeffer, K., and Bleul, C. C. (2003). Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTbetaR. J. Exp. Med. 198, 757-769.
15. Bren, G. D., Solan, N. J., Miyoshi, H., Pennington, K. N., Pobst, L. J., and Paya, C. V. (2001). Transcription of the RelB gene is regulated by NF-kappaB. Oncogene 20, 7722-7733.
16. Burchill, M., Yang, J., Vang, K., Moon, J., Chu, H., Lio, C., Vegoe, A., Hsieh, C., Jenkins, M., and Farrar, M. (2008). Linked T cell receptor and cytokine signaling govern thedevelopment of the regulatory T cell repertoire. Immunity 28, 112-121.
17. Burkly, L., Hession, C., Ogata, L., Reilly, C., Marconi, L., Olson, D., Tizard, R., Cate, R., and Lo, D. (1995). Expression of relB is required for the development of thymic medulla and dendritic cells. Nature 373, 531-536.
18. Chin, R. K., Lo, J. C., Kim, O., Blink, S. E., Christiansen, P. A., Peterson, P., Wang, Y., Ware, C., and Fu, Y. X. (2003). Lymphotoxin pathway directs thymic Aire expression. Nat. Immunol. 4, 1121-1127.
19. Chin, R. K., Zhu, M., Christiansen, P. A., Liu, W., Ware, C., Peltonen, L., Zhang, X., Guo, L., Han, S., Zheng, B., and Fu, Y X. (2006). Lymphotoxin pathway-directed, autoimmune regulator-independent central tolerance to arthritogenic collagen. J. Immunol. 177, 290-297.
20. Consortium, F.-G. A. (1997). An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet. 17, 399-403.
21. Daniely, D., Kern, J., Cebula, A., and Ignatowicz, L. (2010). Diversity of TCRs on natural Foxp3+ T cells in mice lacking Aire expression. J. Immunol. 184, 6865-6873.
22. Darnay, B. G., Besse, A., Poblenz, A. T., Lamothe, B., and Jacoby, J. J. (2007). TRAFs in RANK signaling. Adv. Exp. Med. Biol. 597, 152-159.
23. Dejardin, E., Droin, N. M., Delhase, M., Haas, E., Cao, Y., Makris, C., Li, Z. W., Karin, M., Ware, C. E, and Green, D. R. (2002). The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways. Immunity 17, 525-535.
24. Derbinski, J., Gäbler, J., Brors, B., Tierling, S., Jonnakuty, S., Hergenhahn, M., Peltonen, L., Walter, J., and Kyewski, B. (2005). Promiscuous gene expression in thymic epithelial cells is regulatedat multiple levels. J. Exp. Med. 202, 33-45.
25. Derbinski, J., Pinto, S., Rösch, S., Hexel, K., and Kyewski, B. (2008). Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism. Proc. Natl. Acad. Sci. U.S.A. 105, 657-662.
26. DeVoss, J., Hou, Y., Johannes, K., Lu, W., Liou, G. I., Rinn, J., Chang, H., Caspi, R. R., Caspi, R., Fong, L., and Anderson, M. S. (2006). Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J. Exp. Med. 203, 2727-2735.
27. Dooley, J., Erickson, M., and Farr, A. G. (2008). Alterations of the medullary epithelial compartment in the Aire-deficient thymus: implications for programs of thymic epithelial differentiation. J. Immunol. 181, 5225-5232.
28. Dougall, W. C., Glaccum, M., Charrier, K., Rohrbach, K., Brasel, K., De Smedt, T., Daro, E., Smith, J., Tometsko, M. E., Maliszewski, C. R., Armstrong, A., Shen, V., Bain, S., Cosman, D., Anderson, D., Morrissey, P. J., Peschon, J. J., and Schuh, J. (1999). RANK is essential for osteoclast and lymph node development. Genes Dev. 13, 2412-2424.
29. Drayton, D. L., Liao, S., Mounzer, R. H., and Ruddle, N. H. (2006). Lymphoid organ development: from ontogeny to neogenesis. Nat. Immunol. 7, 344-353.
30. Duheron, V., Hess, E., Duval, M., Decossas, M., Castaneda, B., Klöpper, J. E., Amoasii, L., Barbaroux, J. B., Williams, I. R., Yagita, H., Penninger, J., Choi, Y, Lezot, F., Groves, R., Paus, R., and Mueller, C. G. (2011). Receptor activator of NF-kappaB(RANK) stimulates the prolif eration of epithelial cells of the epidermo-pilosebaceous unit. Proc. Natl. Acad. Sci. U.S.A. 108, 5342-5347.
31. Dunn, R. J., Luedecker, C. J., Haugen, H. S., Clegg, C. H., and Farr, A. G. (1997). Thymic overexpression of CD40 ligand disrupts normal thymic epithelial organization. J. Histochem. Cytochem. 45, 129-141.
32. Elgueta, R., Benson, M. J., de Vries, V. C., Wasiuk, A., Guo, Y., and Noelle, R. J. (2009). Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol. Rev. 229, 152-172.
33. Fan, Y., Rudert, W. A., Grupillo, M., He, J., Sisino, G., and Trucco, M. (2009). Thymus-specific deletion of insulin induces autoimmune diabetes. EMBOJ. 28, 2812-2824.
34. Fata, J. E., Kong, Y. Y., Li, J., Sasaki, T., Irie-Sasaki, J., Moorehead, R. A., Elliott, R., Scully, S., Voura, E. B., Lacey, D. L., Boyle, W. J., Khokha, R., and Penninger, J. M. (2000). The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103, 41-50.
35. Foy, T. M., Page, D. M., Waldschmidt, T. J., Schoneveld, A., Laman, J. D., Masters, S. R., Tygrett, L., Ledbetter, J. A., Aruffo, A., Claassen, E., Xu, J. C., Flavell, R. A., Oehen, S., Hedrick, S. M., and Noelle, R. J. (1995). An essential role for gp39, the ligand for CD40, in thymic selection. J. Exp. Med. 182, 1377-1388.
36. Franzoso, G., Carlson, L., Xing, L., Poljak, L., Shores, E. W., Brown, K. D., Leonardi, A., Tran, T., Boyce, B. F., and Siebenlist, U. (1997). Requirement for NF-kappaB in osteoclast and B-cell development. GenesDev. 11, 3482-3496.
37. Gäbler, J., Arnold, J., and Kyewski, B. (2007). Promiscuous gene expression and the developmental dynamics of medullary thymic epithelial cells. Eur. J. Immunol. 37, 3363-3372.
38. Gallegos, A. M., and Bevan, M. J. (2004). Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J. Exp. Med. 200, 1039-1049.
39. Galy, A. H., and Spits, H. (1992). CD40 is functionally expressed on human thymic epithelial cells. J. Immunol. 149, 775-782.
40. Gill, J., Malin, M., Sutherland, J., Gray, D., Hollander, G., and Boyd, R. (2003). Thymic generation and regeneration. Immunol. Rev. 195, 28-50.
41. Gillard, G. O., Dooley, J., Erickson, M., Peltonen, L., and Farr, A. G. (2007). Aire-dependent alterations in medullary thymic epithelium indicate a role for Aire in thymic epithelial differentiation. J. Immunol. 178, 3007-3015.
42. Giraud, M., Taubert, R., Vandiedonck, C., Ke, X., Lévi-Strauss, M., Pagani, E, Baralle, F. E., Eymard, B., Tranchant, C., Gajdos, P., Vincent, A., Willcox, N., Beeson, D., Kyewski, B., and Garchon, H. J. (2007). An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature 448, 934-937.
43. Gray, D. H., Seach, N., Ueno, T., Milton, M. K., Liston, A., Lew, A. M., Goodnow, C. C., and Boyd, R. L. (2006). Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 108, 3777-3785.
44. Gray, D., Abramson, J., Benoist, C., and Mathis, D. (2007). Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire. J. Exp. Med. 204, 2521-2528.
45. Guerder, S., Viret, C., Luche, H., Ardouin, L., and Malissen, B. (2012). Differential processing of self-antigens by subsets of thymic stromal cells. Curr. Opin. Immunol. 24, 99-104.
46. Hamazaki, Y., Fujita, H., Kobayashi, T., Choi, Y., Scott, H. S., Matsumoto, M., and Minato, N. (2007). Medullary thymic epithelial cells expressing Aire represent a unique lineage derived from cells expressing claudin. Nat. Immunol. 8, 304-311.
47. Hayden, M., and Ghosh, S. (2008). Shared principles in NF-kappaB signaling. Cell 132, 344-362.
48. Hehlgans, T., and Pfeffer, K. (2005). The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfam-ily: players, rules and the games. Immunology 115, 1-20.
49. Hikosaka, Y., Nitta, T., Ohigashi, I., Yano, K., Ishimaru, N., Hayashi, Y., Matsumoto, M., Matsuo, K., Penninger, J., Takayanagi, H., Yokota, Y., Yamada, H., Yoshikai, Y., Inoue, J., Akiyama, T., and Takahama, Y (2008). The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 29, 438-450.
50. Hinterberger, M., Aichinger, M., da Costa, O., Voehringer, D., Hoffmann, R., and Klein, L. (2010). Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance. Nat. Immunol. 11, 512-519.
51. Holländer, G., Gill, J., Zuklys, S., Iwanami, N., Liu, C., and Takahama, Y (2006). Cellular and molecular events during early thymus development. Immunol. Rev. 209, 28-46.
52. Hong, C., Luckey, M. A., and Park, J. H. (2012). Intrathymic IL-7, The where, when, and why of IL-7 signaling during T cell development. Semin. Immunol. 24, 151-158.
53. Hozumi, K., Mailhos, C., Negishi, N., Hirano, K., Yahata, T., Ando, K., Zuklys, S., Holländer, G. A., Shima, D. T., and Habu, S. (2008). Delta-like 4 is indispensable in thymic environment specific for T cell development. J. Exp. Med. 205, 2507-2513.
54. Hsieh, C. S., Lee, H. M., and Lio, C. W. (2012). Selection of regulatory T cells in the thymus. Nat. Rev. Immunol. 12, 157-167.
55. Inoue, J., Gohda, J., and Akiyama, T. (2007). Characteristics and biological functions of TRAF6. Adv. Exp. Med. Biol. 597, 72-79.
56. Irla, M., Hugues, S., Gill, J., Nitta, T., Hikosaka, Y., Williams, I. R., Hubert, F. X., Scott, H. S., Takahama, Y., Holländer, G. A., and Reith, W. (2008). Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity. Immunity 29, 451-463.
57. Josefowicz, S. Z., Lu, L. F., and Rudensky, A. Y (2012). Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531-564.
58. 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., and Matsumoto, M. (2004). NF-kappa B-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner. J. Immunol. 172, 2067-2075.
59. Kim, D., Mebius, R. E., MacMicking, J. D., Jung, S., Cupedo, T., Castellanos, Y., Rho, J., Wong, B. R., Josien, R., Kim, N., Rennert, P. D., and Choi, Y (2000). Regulation of peripheral lymph node genesis by the tumor necrosis factor family member TRANCE. J. Exp. Med. 192, 1467-1478.
60. 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., and Matsumoto, M. (2006). Essential role of IkappaB kinase alpha in thymic organogen-esis required for the establishment of self-tolerance. J. Immunol. 176, 3995-4002.
61. Klein, L., Hinterberger, M., Wirnsberger, G., and Kyewski, B. (2009). Antigen presentation in the thymus for positive selection and central tolerance induction. Nat. Rev. Immunol. 9, 833-844.
62. Koble, C., and Kyewski, B. (2009). The thymic medulla: a unique microen-vironment for intercellular self-antigen transfer. J. Exp. Med. 206, 1505-1513.
63. Koch, U., Fiorini, E., Benedito, R., Besseyrias, V., Schuster-Gossler, K., Pierres, M., Manley, N. R., Duarte, A., Macdonald, H. R., and Radtke, F. (2008). Delta-like 4 is the essential, nonredundant ligand for Notch 1 during thymic T cell lineage commitment. J. Exp. Med. 205, 2515-2523.
64. Kong, Y Y, Yoshida, H., Sarosi, I., Tan, H. L., Timms, E., Capparelli, C., Morony, S., Oliveira-dos-Santos, A. J., Van, G., Itie, A., Khoo, W., Wakeham, A., Dunstan, C. R., Lacey, D. L., Mak, T. W., Boyle, W. J., and Penninger, J. M. (1999). OPGL is a key regulator of osteoclastogen-esis, lymphocyte development and lymph-node organogenesis. Nature 397, 315-323.
65. Kumanogoh, A., Wang, X., Lee, I., Watanabe, C., Kamanaka, M., Shi, W., Yoshida, K., Sato, T., Habu, S., Itoh, M., Sakaguchi, N., Sakaguchi, S., and Kikutani, H. (2001). Increased T cell autoreac-tivity in the absence of CD40-CD40 ligand interactions: a role of CD40 in regulatory T cell development. J. Immunol. 166, 353-360.
66. Kurobe, H., Liu, C., Ueno, T., Saito, F., Ohigashi, I., Seach, N., Arakaki, R., Hayashi, Y., Kitagawa, T., Lipp, M., Boyd, R. L., and Takahama, Y. (2006). CCR7-dependent cortex-to-medulla migration of positively selected thymocytes is essential for establishing central tolerance. Immunity 24, 165-177.
67. Kyewski, B., and Klein, L. (2006). A central role for central tolerance. Annu. Rev. Immunol. 24, 571-606.
68. Laan, M., Kisand, K., Kont, V, Moll, K., Tserel, L., Scott, H. S., and Peterson, P. (2009). Autoimmune regulator deficiency results in decreased expression of CCR4 and CCR7 ligands and in delayed migration of CD4+ thymocytes.J. Immunol. 183, 7682-7691.
69. Lee, H. M., and Hsieh, C. S. (2009). Rare development of Foxp3+ thymocytes in the CD4+CD8+ subset. J. Immunol. 183, 2261-2266.
70. Lei, Y., Ripen, A. M., Ishimaru, N., Ohigashi, I., Nagasawa, T., Jeker, L. T., Bösl, M. R., Holländer, G. A., Hayashi, Y., Malefyt, R de. W., Nitta, T., and Takahama, Y (2011). Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. J. Exp. Med. 208, 383-394.
71. Lio, C., and Hsieh, C. (2008). A two-step process for thymic regulatory T cell development. Immunity 28, 100-111.
72. Lomada, D., Liu, B., Coghlan, L., Hu, Y., and Richie, E. R. (2007). Thymus medulla formation and central tolerance are restored in IKKalpha-/- mice that express an IKKalpha transgene in keratin 5+ thymic epithelial cells. J. Immunol. 178, 829-837.
73. Ma, D. Y., and Clark, E. A. (2009). The role of CD40 and CD154/CD40L in dendritic cells. Semin. Immunol. 21, 265-272.
74. Martín-Gayo, E., Sierra-Filardi, E., Corbí, A. L., and Toribio, M. L. (2010). Plasmacytoid dendritic cells resident in human thymus drive natural Treg cell development. Blood 115, 5366-5375.
75. Mathis, D., and Benoist, C. (2004). Back to central tolerance. Immunity 20, 509-516.
76. Mathis, D., and Benoist, C. (2009). Aire. Annu. Rev. Immunol. 27, 287-312.
77. Mebius, R. E. (2003). Organogenesis of lymphoid tissues. Nat. Rev. Immunol. 3, 292-303.
78. Michels, A. W., and Gottlieb, P. A. (2010). Autoimmune polyglandular syndromes. Nat. Rev. Endocrinol. 6, 270-277.
79. Miyawaki, S., Nakamura, Y., Suzuka, H., Koba, M., Yasumizu, R., Ikehara, S., and Shibata, Y (1994). A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice. Eur. J. Immunol. 24, 429-434.
80. 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, J. M., Inoue, J., Akiyama, T., and Matsumoto, M. (2011). Lymphotoxin signal promotes thymic organogenesis by eliciting RANK expression in the embryonic thymic stroma. J. Immunol. 186, 5047-5057.
81. Nagamine, K., Peterson, P., Scott, H., Kudoh, J., Minoshima, S., Heino, M., Krohn, K., Lalioti, M., Mullis, P., Antonarakis, S., Kawasaki, K., Asakawa, S., Ito, F., and Shimizu, N. (1997). Positional cloning of the APECED gene. Nat. Genet. 17, 393-398.
82. Nishikawa, Y., Hirota, F., Yano, M., Kitajima, H., Miyazaki, J., Kawamoto, H., Mouri, Y., and Matsumoto, M. (2010). Biphasic Aire expression in early embryos and in medullary thymic epithelial cells before end-stage terminal differentiation. J. Exp. Med. 207, 963-971.
83. Ohshima, D., Qin, J., Konno, H., Hirosawa, A., Shiraishi, T., Yanai, H., Shimo, Y., Shinzawa, M., Akiyama, N., Yamashita, R., Nakai, K., Akiyama, T., and Inoue, J. (2011). RANK signaling induces interferon-stimulated genes in the fetal thymic stroma. Biochem. Biophys. Res. Commun. 408, 530-536.
84. Peterson, P., Org, T., and Rebane, A. (2008). Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat. Rev. Immunol. 8, 948-957.
85. Qin, J., Konno, H., Ohshima, D., Yanai, H., Motegi, H., Shimo, Y., Hirota, F., Matsumoto, M., Takaki, S., Inoue, J., and Akiyama, T. (2007). Developmental stage-dependent collaboration between the TNF receptor-associated factor 6 and lymphotoxin pathways for B cell follicle organization in secondary lymphoid organs. J. Immunol. 179, 6799-6807.
86. Randall, T. D., Carragher, D. M., and Rangel-Moreno, J. (2008). Development of secondary lymphoid organs. Annu. Rev. Immunol. 26, 627-650.
87. Roberts, N. A., White, A. J., Jenkinson, W. E., Turchinovich, G., Nakamura, K., Withers, D. R., McConnell, F. M., Desanti, G. E., Benezech, C., Parnell, S. M., Cunningham, A. F., Paolino, M., Penninger, J. M., Simon, A. K., Nitta, T., Ohigashi, I., Takahama, Y., Caamano, J. H., Hayday, A. C., Lane, P. J., Jenkinson, E. J., and Anderson, G. (2012). Rank signaling links the development of invariant gd T cell progenitors and Aire(+) medullary epithelium. Immunity 36, 427-437.
88. Rodewald, H. R., Paul, S., Haller, C., Bluethmann, H., and Blum, C. (2001). Thymus medulla consisting of epithelial islets each derived from a single progenitor. Nature 414, 763-768.
89. Rossi, S. W., Jenkinson, W E., Anderson, G., and Jenkinson, E. J. (2006). Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 441, 988-991.
90. Rossi, S., Kim, M., Leibbrandt, A., Parnell, S., Jenkinson, W., Glanville, S., McConnell, F., Scott, H., Penninger, J., Jenkinson, E., Lane, P., and Anderson, G. (2007). RANK signals from CD4(+)3(-) inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J. Exp. Med. 204, 1267-1272.
91. Ruggiero, G., Martinez Cáceres, E., Voordouw, A., Noteboom, E., Graf, D., Kroczek, R. A., and Spits, H. (1996). CD40 expressed on thymic epithelial cells provides costimula-tion for proliferation but not for apoptosis of human thymocytes. J. Immunol. 156, 3737-3746.
92. Seach, N., Ueno, T., Fletcher, A. L., Lowen, T., Mattesich, M., Engwerda, C. R., Scott, H. S., Ware, C. F., Chidgey, A. P., Gray, D. H., and Boyd, R. L. (2008). The lymphotoxin pathway regulates Aire-independent expression of ectopic genes and chemokines in thymic stromal cells. J. Immunol. 180, 5384-5392.
93. Shakib, S., Desanti, G. E., Jenkinson, W. E., Parnell, S. M., Jenkinson, E. J., and Anderson, G. (2009). Checkpoints in the development of thymic cortical epithelial cells. J. Immunol. 182, 130-137.
94. Shimo, Y., Yanai, H., Ohshima, D., Qin, J., Motegi, H., Maruyama, Y., Hori, S., Inoue, J., and Akiyama, T. (2011). TRAF6 directs commitment to regulatory T cells in thymocytes. Genes Cells 16, 437-447.
95. Shinzawa, M., Maruyama, Y., Qin, J., Akiyama, N., Miyauchi, M., Yanai, H., Takami, M., Inoue, J., and Akiyama, T. (2011). Splenic extramedullary hemopoiesis caused by a dysfunctional mutation in the NF-kB-inducing kinase gene. Biochem. Biophys. Res. Commun. 414, 773-778.
96. Spence, P. J., and Green, E. A. (2008). Foxp3+ regulatory T cells promiscuously accept thymic signals critical for their development. Proc. Natl. Acad Sci. U.S.A. 105, 973-978.
97. Takahama, Y (2006). Journey through the thymus: stromal guides for T-cell development and selection. Nat. Rev. Immunol. 6, 127-135.
98. Tykocinski, L. O., Sinemus, A., Rezavandy, E., Weiland, Y., Baddeley, D., Cremer, C., Sonntag, S., Willecke, K., Derbinski, J., and Kyewski, B. (2010). Epigenetic regulation of promiscuous gene expression in thymic medullary epithelial cells. Proc. Natl Acad. Sci. U.S.A. 107, 19426-19431.
99. Ueno, T., Hara, K., Willis, M. S., Malin, M. A., Höpken, U. E., Gray, D. H., Matsushima, K., Lipp, M., Springer, T. A., Boyd, R. L., Yoshie, O., and Takahama, Y (2002). Role for CCR7 ligands in the emigration of newly generated T lymphocytes from the neonatal thymus. Immunity 16, 205-218.
100. Ueno, T., Saito, F., Gray, D. H., Kuse, S., Hieshima, K., Nakano, H., Kakiuchi, T., Lipp, M., Boyd, R. L., and Takahama, Y (2004). CCR7 signals are essential for cortex-medulla migration of developing thymocytes. J. Exp. Med. 200, 493-505.
101. Vallabhapurapu, S., and Karin, M. (2009). Regulation and function of NF-kappaB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693-733.
102. Venanzi, E. S., Gray, D. H., Benoist, C., and Mathis, D. (2007). Lymphotoxin pathway and Aire influences on thymic medullary epithelial cells are unconnected. J. Immunol. 179, 5693-5700.
103. Villaseñor, J., Besse, W., Benoist, C., and Mathis, D. (2008). Ectopic expression of peripheral-tissue antigens in the thymic epithelium: probabilistic, monoallelic, misinitiated. Proc. Natl Acad. Sci. U.S.A. 105, 15854-15859.
104. Weih, F., Carrasco, D., Durham, S., Barton, D., Rizzo, C., Ryseck, R., Lira, S., and Bravo, R. (1995). Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell 80, 331-340.
105. White, A. J., Nakamura, K., Jenkinson, W E., Saini, M., Sinclair, C., Seddon, B., Narendran, P., Pfeffer, K., Nitta, T., Takahama, Y., Caamano, J. H., Lane, P. J., Jenkinson, E. J., and Anderson, G. (2010). Lymphotoxin signals from positively selected thymocytes regulate the terminal differentiation of medullary thymic epithelial cells. J. Immunol. 185, 4769-4776.
106. White, A. J., Withers, D. R., Parnell, S. M., Scott, H. S., Finke, D., Lane, P. J., Jenkinson, E. J., and Anderson, G. (2008). Sequential phases in the development of Aire-expressing medullary thymic epithelial cells involve distinct cellular input. Eur. I Immunol. 38, 942-947.
107. Williams, J. A., Sharrow, S. O., Adams, A. J., and Hodes, R. J. (2002). CD40 ligand functions non-cell autonomously to promote deletion of self-reactive thymocytes. J. Immunol. 168, 2759-2765.
108. Wing, K., and Sakaguchi, S. (2010). Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat. Immunol. 11, 7-13.
109. Wong, B. R., Josien, R., Lee, S. Y., Sauter, B., Li, H. L., Steinman, R. M., and Choi, Y (1997). TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed inScells, SST, is a dendritic cell-specific survival factor. J. Exp. Med. 186, 2075-2080.
110. 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., and Matsumoto, M. (2008). Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance. J. Exp. Med. 205, 2827-2838.
111. Yasuda, H., Shima, N., Nakagawa, N., Yamaguchi, K., Kinosaki, M., Mochizuki, S., Tomoyasu, A., Yano, K., Goto, M., Murakami, A., Tsuda, E., Morinaga, T., Higashio, K., Udagawa, N., Takahashi, N., and Suda, T. (1998). Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl. Acad Sci. U.S.A. 95, 3597-3602.
112. Zhang, B., Wang, Z., Ding, J., Peterson, P., Gunning, W. T., and Ding, H. F. (2006). NF-kappaB2 is required for the control of autoimmunity by regulating the development of medullary thymic epithelial cells. J. Biol. Chem. 281, 38617-38624.
113. Zhang, X., Wang, H., Claudio, E., Brown, K., and Siebenlist, U. (2007). A role for the IkappaB family member Bcl-3 in the control of central immunologic tolerance. Immunity 27, 438-452.
114. Zhu, M., Brown, N. K., and Fu, Y. X. (2010). Direct and indirect roles of the LTbetaR pathway in central tolerance induction. Trends Immunol. 31, 325-331.
115. Zhu, M., Chin, R. K., Christiansen, P. A., Lo, J. C., Liu, X., Ware, C., Siebenlist, U., and Fu, Y X. (2006). NF-kappaB2 is required for the establishment of central tolerance through an Aire-dependent pathway. J. Clin. Invest. 116, 2964-2971.
116. Zhu, M., Chin, R. K., Tumanov, A. V., Liu, X., and Fu, Y X. (2007). Lymphotoxin beta receptor is required for the migration and selection of autoreactive T cells in thymic medulla. J. Immunol. 179, 8069-8075.
117. Zuklys, S., Balciunaite, G., Agarwal, A., Fasler-Kan, E., Palmer, E., and Holländer, G. A. (2000). Normal thymic architecture and negative selection are associated with Aire expression, the gene defective in the autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). J. Immunol. 165, 1976-1983.