Thymic epithelial cell development and differentiation: cellular and molecular regulation

Lina Sun, Haiying Luo, Hongran Li, Yong Zhao()

PDF(443 KB)
PDF(443 KB)
Protein Cell ›› 2013, Vol. 4 ›› Issue (5) : 342-355. DOI: 10.1007/s13238-013-3014-0
REVIEW

Thymic epithelial cell development and differentiation: cellular and molecular regulation

  • Lina Sun, Haiying Luo, Hongran Li, Yong Zhao()
Author information +
History +

Abstract

Thymic epithelial cells (TECs) are one of the most important components in thymic microenvironment supporting thymocyte development and maturation. TECs, composed of cortical and medullary TECs, are derived from a common bipotent progenitor, mediating thymocyte positive and negative selections. Multiple levels of signals including intracellular signaling networks and cell-cell interaction are required for TEC development and differentiation. Transcription factors Foxn1 and autoimmune regulator (Aire) are powerful regulators promoting TEC development and differentiation. Crosstalks with thymocytes and other stromal cells for extrinsic signals like RANKL, CD40L, lymphotoxin, fi broblast growth factor (FGF) and Wnt are also defi nitely required to establish a functional thymic microenvironment. In this review, we will summarize our current understanding about TEC development and differentiation, and its underlying multiple signal pathways.

Keywords

thymus / thymic epithelial cells / Aire / Foxn1 / TNFR / NF-κB / FGFs

Cite this article

Download citation ▾
Lina Sun, Haiying Luo, Hongran Li, Yong Zhao. Thymic epithelial cell development and differentiation: cellular and molecular regulation. Prot Cell, 2013, 4(5): 342‒355 https://doi.org/10.1007/s13238-013-3014-0

References

[1] Akiyama, T., Maeda, S., Yamane, S., Ogino, K., Kasai, M., Kajiura, F., Matsumoto, M., and Inoue, J. (2005). Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 308, 248-251 .10.1126/science.1105677
[2] Akiyama, T., Shimo, Y., Yanai, H., Qin, J., Ohshima, D., Maruyama, Y., Asaumi, Y., Kitazawa, J., Takayanagi, H., Penninger, J.M., . (2008). The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29, 423-437 .10.1016/j.immuni.2008.06.015
[3] Akiyama, T., Shinzawa, M., and Akiyama, N. (2012). TNF receptor family signaling in the development and functions of medullary thymic epithelial cells. Front Immunol 3, 278.10.3389/fimmu.2012.00278
[4] Alexandropoulos, K., and Danzl, N.M. (2012). Thymic epithelial cells: antigen presenting cells that regulate T cell repertoire and tolerance development. Immunol Res 54, 177-190 .10.1007/s12026-012-8301-y
[5] Alexandropoulos, K., Donlin, L.T., Xing, L., and Regelmann, A.G. (2003). Sin: good or bad? AT lymphocyte perspective. Immunol Rev 192, 181-195 .10.1034/j.1600-065X.2003.00021.x
[6] Alpdogan, O., Hubbard, V.M., Smith, O.M., Patel, N., Lu, S., Goldberg, G.L., Gray, D.H., Feinman, J., Kochman, A.A., Eng, J.M., . (2006). Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration. Blood 107, 2453-2460 .10.1182/blood-2005-07-2831
[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 .10.1016/j.it.2012.03.005
[8] Anderson, M.S., Venanzi, E.S., Klein, L., Chen, Z., Berzins, S.P., Turley, S.J., von Boehmer, H., Bronson, R., Dierich, A., Benoist, C., . (2002). Projection of an immunological self shadow within the thymus by the aire protein. Science 298, 1395-1401 .10.1126/science.1075958
[9] Auerbach, R. (1960). Morphogenetic interactions in the development of the mouse thymus gland. Dev Biol 2, 271-284 .10.1016/0012-1606(60)90009-9
[10] Balciunaite, G., Keller, M.P., Balciunaite, E., Piali, L., Zuklys, S., Mathieu, Y.D., Gill, J., Boyd, R., Sussman, D.J., and Hollander, G.A. (2002). Wnt glycoproteins regulate the expression of FoxN1, the gene defective in nude mice. Nat Immunol 3, 1102-1108 .10.1038/ni850
[11] Basak, S., and Hoffmann, A. (2008). Crosstalk via the NF-kappaB signaling system. Cytokine Growth Factor Rev 19, 187-197 .10.1016/j.cytogfr.2008.04.005
[12] Baxter, R.M., and Brissette, J.L. (2002). Role of the nude gene in epithelial terminal differentiation. J Invest Dermatol 118, 303-309 .10.1046/j.0022-202x.2001.01662.x
[13] Bennett, A.R., Farley, A., Blair, N.F., Gordon, J., Sharp, L., and Blackburn, C.C. (2002). Identifi cation and characterization of thymic epithelial progenitor cells. Immunity 16, 803-814 .10.1016/S1074-7613(02)00321-7
[14] Berent-Maoz, B., Montecino-Rodriguez, E., Signer, R.A., and Dorshkind, K. (2012). Fibroblast growth factor-7 partially reverses murine thymocyte progenitor aging by repression of Ink4a. Blood 119, 5715-5721 .10.1182/blood-2011-12-400002
[15] Blackburn, C.C., Augustine, C.L., Li, R., Harvey, R.P., Malin, M.A., Boyd, R.L., Miller, J.F., and Morahan, G. (1996). The nu gene acts cell-autonomously and is required for differentiation of thymic epithelial progenitors. Proc Natl Acad Sci USA 93, 5742-5746 .10.1073/pnas.93.12.5742
[16] Bleul, C.C., and Boehm, T. (2005). BMP signaling is required for normal thymus development. J Immunol 175, 5213-5221 .
[17] Bleul, C.C., Corbeaux, T., Reuter, A., Fisch, P., Monting, J.S., and Boehm, T. (2006). Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 441, 992-996 .10.1038/nature04850
[18] Bockman, D.E., and Kirby, M.L. (1984). Dependence of thymus development on derivatives of the neural crest. Science 223, 498-500 .10.1126/science.6606851
[19] 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 .10.1084/jem.20030794
[20] Bravo-Nuevo, A., O'Donnell, R., Rosendahl, A., Chung, J.H., Benjamin, L.E., and Odaka, C.RhoB defi ciency in thymic medullary epithelium leads to early thymic atrophy. Int Immunol 23, 593-600 .10.1093/intimm/dxr064
[21] Burkly, L., Hession, C., Ogata, L., Reilly, C., Marconi, L.A., 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 .10.1038/373531a0
[22] Calderon, L., and Boehm, T. (2012). Synergistic, context-dependent, and hierarchical functions of epithelial components in thymic microenvironments. Cell 149, 159-172 .10.1016/j.cell.2012.01.049
[23] Candi, E., Dinsdale, D., Rufini, A., Salomoni, P., Knight, R.A., Mueller, M., Krammer, P.H., and Melino, G. (2007a). TAp63 and DeltaNp63 in cancer and epidermal development. Cell Cycle 6, 274-285 .10.4161/cc.6.3.3797
[24] Candi, E., Rufini, A., Terrinoni, A., Giamboi-Miraglia, A., Lena, A.M., Mantovani, R., Knight, R., and Melino, G. (2007b). DeltaNp63 regulates thymic development through enhanced expression of FgfR2 and Jag2. Proc Natl Acad Sci U S A 104, 11999-12004 .10.1073/pnas.0703458104
[25] Chen, L., Xiao, S., and Manley, N.R. (2009). Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner. Blood 113, 567-574 .10.1182/blood-2008-05-156265
[26] Cheng, L., Guo, J., Sun, L., Fu, J., Barnes, P.F., Metzger, D., Chambon, P., Oshima, R.G., Amagai, T., and Su, D.M. (2010). Postnatal tissue-specific disruption of transcription factor FoxN1 triggers acute thymic atrophy. J Biol Chem 285, 5836-5847 .10.1074/jbc.M109.072124
[27] 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 .10.1038/ni982
[28] Chin, R.K., Zhu, M., Christiansen, P.A., Liu, W., Ware, C., Peltonen, L., Zhang, X., Guo, L., Han, S., Zheng, B., . (2006). Lymphotoxin pathway-directed, autoimmune regulator-independent central tolerance to arthritogenic collagen. J Immunol 177, 290-297 .
[29] Corbeaux, T., Hess, I., Swann, J.B., Kanzler, B., Haas-Assenbaum, A., and Boehm, T. (2010). Thymopoiesis in mice depends on a Foxn1- positive thymic epithelial cell lineage. Proc Natl Acad Sci USA 107, 16613-16618 .10.1073/pnas.1004623107
[30] Cordier, A.C., and Heremans, J.F. (1975). Nude mouse embryo: ectodermal nature of the primordial thymic defect. Scand J Immunol 4, 193-196 .10.1111/j.1365-3083.1975.tb02616.x
[31] Danso-Abeam, D., Humblet-Baron, S., Dooley, J., and Liston, A. (2011). Models of aire-dependent gene regulation for thymic negative selection. Front Immunol 2, 14.10.3389/fimmu.2011.00014
[32] Danzl, N.M., Donlin, L.T., and Alexandropoulos, K. (2010). Regulation of medullary thymic epithelial cell differentiation and function by the signaling protein Sin. J Exp Med 207, 999-1013 .10.1084/jem.20092384
[33] Derbinski, J., Gabler, 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 regulated at multiple levels. J Exp Med 202, 33-45 .10.1084/jem.20050471
[34] Derbinski, J., Pinto, S., Rosch, 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 USA 105, 657-662 .10.1073/pnas.0707486105
[35] Dooley, J., Erickson, M., and Farr, A.G. (2008). Alterations of the medullary epithelial compartment in the Aire-defi cient thymus: implications for programs of thymic epithelial differentiation. J Immunol 181, 5225-5232 .
[36] Endres, R., Alimzhanov, M.B., Plitz, T., Futterer, A., Kosco-Vilbois, M.H., Nedospasov, S.A., Rajewsky, K., and Pfeffer, K. (1999). Mature follicular dendritic cell networks depend on expression of lymphotoxin beta receptor by radioresistant stromal cells and of lymphotoxin beta and tumor necrosis factor by B cells. J Exp Med 189, 159-168 .10.1084/jem.189.1.159
[37] Erickson, M., Morkowski, S., Lehar, S., Gillard, G., Beers, C., Dooley, J., Rubin, J.S., Rudensky, A., and Farr, A.G. (2002). Regulation of thymic epithelium by keratinocyte growth factor. Blood 100, 3269-3278 .10.1182/blood-2002-04-1036
[38] Farr, A.G., Dooley, J.L., and Erickson, M. (2002). Organization of thymic medullary epithelial heterogeneity: implications for mechanisms of epithelial differentiation. Immunol Rev 189, 20-27 .10.1034/j.1600-065X.2002.18903.x
[39] Flomerfelt, F.A., ElKassar, N., Gurunathan, C., Chua, K.S., League, S.C., Schmitz, S., Gershon, T.R., Kapoor, V., Yan, X.Y., Schwartz, R.H., . (2010). Tbata modulates thymic stromal cell proliferation and thymus function. J Exp Med 207, 2521-2532 .10.1084/jem.20092759
[40] Flomerfelt, F.A., Kim, M.G., and Schwartz, R.H. (2000). Spatial, a gene expressed in thymic stromal cells, depends on three-dimensional thymus organization for its expression. Genes Immun 1, 391-401 .10.1038/sj.gene.6363695
[41] Frank, D.U., Fotheringham, L.K., Brewer, J.A., Muglia, L.J., Tristani-Firouzi, M., Capecchi, M.R., and Moon, A.M. (2002). An Fgf8 mouse mutant phenocopies human 22q11 deletion syndrome. Develop- ment 129, 4591-4603 .
[42] Futterer, A., Mink, K., Luz, A., Kosco-Vilbois, M.H., and Pfeffer, K. (1998). The lymphotoxin beta receptor controls organogenesis and affi nity maturation in peripheral lymphoid tissues. Immunity 9, 59-70 .10.1016/S1074-7613(00)80588-9
[43] Gabler, 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 .10.1002/eji.200737131
[44] Gardiner, J.R., Jackson, A.L., Gordon, J., Lickert, H., Manley, N.R., and Basson, M.A. (2012). Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis. Development 139, 3456-3466 .10.1242/dev.079400
[45] Gardner, J.M., Fletcher, A.L., Anderson, M.S., and Turley, S.J. (2009). AIRE in the thymus and beyond. Curr Opin Immunol 21, 582-589 .10.1016/j.coi.2009.08.007
[46] 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 .
[47] Gillard, G.O., and Farr, A.G. (2005). Contrasting models of promiscuous gene expression by thymic epithelium. J Exp Med 202, 15-19 .10.1084/jem.20050976
[48] Giraud, M., Yoshida, H., Abramson, J., Rahl, P.B., Young, R.A., Mathis, D., and Benoist, C. (2012). Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells. Proc Natl Acad Sci U S A 109, 535-540 .10.1073/pnas.1119351109
[49] Gommeaux, J., Gregoire, C., Nguessan, P., Richelme, M., Malissen, M., Guerder, S., Malissen, B., and Carrier, A. (2009). Thymus-specifi c serine protease regulates positive selection of a subset of CD4+ thymocytes. Eur J Immunol 39, 956-964 .10.1002/eji.200839175
[50] Gossens, K., Naus, S., Hollander, G.A., and Ziltener, H.J. (2010). De-ficiency of the metalloproteinase-disintegrin ADAM8 is associated with thymic hyper-cellularity. PLoS One 5, e12766.10.1371/journal.pone.0012766
[51] Gravano, D.M., McLelland, B.T., Horiuchi, K., and Manilay, J.O. (2010). ADAM17 deletion in thymic epithelial cells alters aire expression without affecting T cell developmental progression. PLoS One 5, e13528.10.1371/journal.pone.0013528
[52] 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 .10.1084/jem.20070795
[53] 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 .10.1016/j.coi.2012.01.008
[54] Guo, J., Feng, Y., Barnes, P., Huang, F.F., Idell, S., Su, D.M., and Shams, H. (2012). Deletion of FoxN1 in the thymic medullary epithelium reduces peripheral T cell responses to infection and mimics changes of aging. PLoS One 7, e34681.10.1371/journal.pone.0034681
[55] Hale, L.P., and Markert, M.L. (2004). Corticosteroids regulate epithelial cell differentiation and Hassall body formation in the human thymus. J Immunol 172, 617-624 .
[56] 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 .10.1038/ni1438
[57] Heinonen, K.M., Vanegas, J.R., Brochu, S., Shan, J., Vainio, S.J., and Perreault, C. (2011a). Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors. Blood 118, 5163-5173 .10.1182/blood-2011-04-350553
[58] Heinonen, K.M., Vanegas, J.R., Lew, D., Krosl, J., and Perreault, C. (2011b). Wnt4 enhances murine hematopoietic progenitor cell expansion through a planar cell polarity-like pathway. PLoS One 6, e19279.10.1371/journal.pone.0019279
[59] Hikosaka, Y., Nitta, T., Ohigashi, I., Yano, K., Ishimaru, N., Hayashi, Y., Matsumoto, M., Matsuo, K., Penninger, J.M., Takayanagi, H., . (2008). The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 29, 438-450 .10.1016/j.immuni.2008.06.018
[60] Irla, M., Hollander, G., and Reith, W. (2009). Control of central selftolerance induction by autoreactive CD4+ thymocytes. Trends Immunol 31, 71-79 .10.1016/j.it.2009.11.002
[61] Irla, M., Hugues, S., Gill, J., Nitta, T., Hikosaka, Y., Williams, I.R., Hubert, F.X., Scott, H.S., Takahama, Y., Hollander, G.A., . (2008). Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity. Immunity 29, 451-463 .10.1016/j.immuni.2008.08.007
[62] Itoi, M., Kawamoto, H., Katsura, Y., and Amagai, T. (2001). Two distinct steps of immigration of hematopoietic progenitors into the early thymus anlage. Int Immunol 13, 1203-1211 .10.1093/intimm/13.9.1203
[63] Janes, S.M., Ofstad, T.A., Campbell, D.H., Watt, F.M., and Prowse, D.M. (2004). Transient activation of FOXN1 in keratinocytes induces a transcriptional programme that promotes terminal differentiation: contrasting roles of FOXN1 and Akt. J Cell Sci 117, 4157-4168 .10.1242/jcs.01302
[64] Jenkinson, W.E., Bacon, A., White, A.J., Anderson, G., and Jenkinson, E.J. (2008). An epithelial progenitor pool regulates thymus growth. J Immunol 181, 6101-6108 .
[65] Jenkinson, W.E., Jenkinson, E.J., and Anderson, G. (2003). Differential requirement for mesenchyme in the proliferation and maturation of thymic epithelial progenitors. J Exp Med 198, 325-332 .10.1084/jem.20022135
[66] Kajiura, F., Sun, S., Nomura, T., Izumi, K., Ueno, T., Bando, Y., Kuroda, N., Han, H., Li, Y., Matsushima, A., . (2004). NF-kappa B-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner. J Immunol 172, 2067-2075 .
[67] Kinoshita, D., Hirota, F., Kaisho, T., Kasai, M., Izumi, K., Bando, Y., Mouri, Y., Matsushima, A., Niki, S., Han, H., . (2006). Essential role of IkappaB kinase alpha in thymic organogenesis required for the establishment of self-tolerance. J Immunol 176, 3995-4002 .
[68] 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 Notch1 during thymic T cell lineage commitment. J Exp Med 205, 2515-2523 .10.1084/jem.20080829
[69] Kvell, K., Varecza, Z., Bartis, D., Hesse, S., Parnell, S., Anderson, G., Jenkinson, E.J., and Pongracz, J.E. (2010). Wnt4 and LAP2alpha as pacemakers of thymic epithelial senescence. PLoS One 5, e10701.10.1371/journal.pone.0010701
[70] Liiv, I., Haljasorg, U., Kisand, K., Maslovskaja, J., Laan, M., and Peterson, P. (2012). AIRE-induced apoptosis is associated with nuclear translocation of stress sensor protein GAPDH. Biochem Biophys Res Commun 423, 32-37 .10.1016/j.bbrc.2012.05.057
[71] Liu, C., Saito, F., Liu, Z., Lei, Y., Uehara, S., Love, P., Lipp, M., Kondo, S., Manley, N., and Takahama, Y. (2006). Coordination between CCR7- and CCR9-mediated chemokine signals in prevascular fetal thymus colonization. Blood 108, 2531-2539 .10.1182/blood-2006-05-024190
[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] Macedo, C., Evangelista, A.F., Marques, M.M., Octacilio-Silva, S., Donadi, E.A., Sakamoto-Hojo, E.T., and Passos, G.A. (2012). Autoimmune regulator (Aire) controls the expression of microRNAs in medullary thymic epithelial cells. Immunobiology 218, 554-560 .10.1016/j.imbio.2012.06.013
[74] Manley, N.R., and Condie, B.G. (2010). Transcriptional regulation of thymus organogenesis and thymic epithelial cell differentiation. Prog Mol Biol Transl Sci 92, 103-120 .10.1016/S1877-1173(10)92005-X
[75] Martins, V.C., Boehm, T., and Bleul, C.C. (2008). Ltbetar signaling does not regulate Aire-dependent transcripts in medullary thymic epithelial cells. J Immunol 181, 400-407 .
[76] Masuda, K., Germeraad, W.T., Satoh, R., Itoi, M., Ikawa, T., Minato, N., Katsura, Y., van Ewijk, W., and Kawamoto, H. (2009). Notch activation in thymic epithelial cells induces development of thymic microenvironments. Mol Immunol 46, 1756-1767 . 10.1016/j.molimm.2009.01.015
[77] Mathis, D., and Benoist, C. (2009). Aire. Annu Rev Immunol 27, 287- 312.10.1146/annurev.immunol.25.022106.141532
[78] Min, D., Panoskaltsis-Mortari, A., Kuro, O.M., Hollander, G.A., Blazar, B.R., and Weinberg, K.I. (2007). Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 109, 2529-2537 .10.1182/blood-2006-08-043794
[79] Min, D., Taylor, P.A., Panoskaltsis-Mortari, A., Chung, B., Danilenko, D.M., Farrell, C., Lacey, D.L., Blazar, B.R., and Weinberg, K.I. (2002). Protection from thymic epithelial cell injury by keratinocyte growth factor: a new approach to improve thymic and peripheral T-cell reconstitution after bone marrow transplantation. Blood 99, 4592-4600 .10.1182/blood.V99.12.4592
[80] Mori, K., Itoi, M., Tsukamoto, N., and Amagai, T. (2010). Foxn1 is essential for vascularization of the murine thymus anlage. Cell Immunol 260, 66-69 .10.1016/j.cellimm.2009.09.007
[81] Mouri, Y., Yano, M., Shinzawa, M., Shimo, Y., Hirota, F., Nishikawa, Y., Nii, T., Kiyonari, H., Abe, T., Uehara, H., . (2011). Lymphotoxin signal promotes thymic organogenesis by eliciting RANK expression in the embryonic thymic stroma. J Immunol 186, 5047-5057 .10.4049/jimmunol.1003533
[82] Murata, S., Sasaki, K., Kishimoto, T., Niwa, S., Hayashi, H., Takahama, Y., and Tanaka, K. (2007). Regulation of CD8+ T cell development by thymus-specifi c proteasomes. Science 316, 1349-1353 .10.1126/science.1141915
[83] Murata, S., Takahama, Y., and Tanaka, K. (2008). Thymoproteasome: probable role in generating positively selecting peptides. Curr Opin Immunol 20, 192-196 .10.1016/j.coi.2008.03.002
[84] Nakagawa, T., Roth, W., Wong, P., Nelson, A., Farr, A., Deussing, J., Villadangos, J.A., Ploegh, H., Peters, C., and Rudensky, A.Y. (1998). Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. Science 280, 450-453 .10.1126/science.280.5362.450
[85] Nehls, M., Pfeifer, D., Schorpp, M., Hedrich, H., and Boehm, T. (1994). New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 372, 103-107 .10.1038/372103a0
[86] Nishikawa, Y., Hirota, F., Yano, M., Kitajima, H., Miyazaki, J., Kawamoto, H., Mouri, Y., and Matsumoto, M. (2009). Biphasic Aire expression in early embryos and in medullary thymic epithelial cells before end-stage terminal differentiation. J Exp Med 207, 963-971 .10.1084/jem.20092144
[87] Nowell, C.S., Bredenkamp, N., Tetelin, S., Jin, X., Tischner, C., Vaidya, H., Sheridan, J.M., Stenhouse, F.H., Heussen, R., Smith, A.J., . (2011). Foxn1 regulates lineage progression in cortical and medullary thymic epithelial cells but is dispensable for medullary sublineage divergence. PLoS Genet 7, e1002348.10.1371/journal.pgen.1002348
[88] Oliveira, E.H., Macedo, C., Donate, P.B., Almeida, R.S., Pezzi, N., Nguyen, C., Rossi, M.A., Sakamoto-Hojo, E.T., Donadi, E.A., and Passos, G.A. (2012). Expression profi le of peripheral tissue antigen genes in medullary thymic epithelial cells (mTECs) is dependent on mRNA levels of autoimmune regulator (Aire). Immunobiology 218, 96-104 .10.1016/j.imbio.2012.02.005
[89] Osada, M., Jardine, L., Misir, R., Andl, T., Millar, S.E., and Pezzano, M. (2010). DKK1 mediated inhibition of Wnt signaling in postnatal mice leads to loss of TEC progenitors and thymic degeneration. PLoS One 5, e9062.10.1371/journal.pone.0009062
[90] Patel, S.R., Gordon, J., Mahbub, F., Blackburn, C.C., and Manley, N.R. (2006). Bmp4 and Noggin expression during early thymus and parathyroid organogenesis. Gene Expr Patterns 6, 794-799 .10.1016/j.modgep.2006.01.011
[91] Ramsey, C., Winqvist, O., Puhakka, L., Halonen, M., Moro, A., Kampe, O., Eskelin, P., Pelto-Huikko, M., and Peltonen, L. (2002). Aire de-ficient mice develop multiple features of APECED phenotype and show altered immune response. Hum Mol Genet 11, 397-409 .10.1093/hmg/11.4.397
[92] Revest, J.M., Suniara, R.K., Kerr, K., Owen, J.J., and Dickson, C. (2001). Development of the thymus requires signaling through the fibroblast growth factor receptor R2-IIIb. J Immunol 167, 1954-1961.
[93] Ripen, A.M., Nitta, T., Murata, S., Tanaka, K., and Takahama, Y. (2011). Ontogeny of thymic cortical epithelial cells expressing the thymoproteasome subunit beta5t. Eur J Immunol 41, 1278-1287 .10.1002/eji.201041375
[94] 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., . (2012). Rank signaling links the development of invariant gammadelta T cell progenitors and Aire(+) medullary epithelium. Immunity 36, 427-437 .10.1016/j.immuni.2012.01.016
[95] Rode, I., and Boehm, T. (2012). Regenerative capacity of adult cortical thymic epithelial cells. Proc Natl Acad Sci U S A 109, 3463-3468 . 10.1073/pnas.1118823109
[96] 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 .10.1038/414763a
[97] Rossi, S., Blazar, B.R., Farrell, C.L., Danilenko, D.M., Lacey, D.L., Weinberg, K.I., Krenger, W., and Hollander, G.A. (2002). Keratinocyte growth factor preserves normal thymopoiesis and thymic microenvironment during experimental graft-versus-host disease. Blood 100, 682-691 .10.1182/blood.V100.2.682
[98] Rossi, S.W., Jeker, L.T., Ueno, T., Kuse, S., Keller, M.P., Zuklys, S., Gudkov, A.V., Takahama, Y., Krenger, W., Blazar, B.R., . (2007a). Keratinocyte growth factor (KGF) enhances postnatal Tcell development via enhancements in proliferation and function of thymic epithelial cells. Blood 109, 3803-3811 .10.1182/blood-2006-10-049767
[99] 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 .10.1038/nature04813
[100] Rossi, S.W., Kim, M.Y., Leibbrandt, A., Parnell, S.M., Jenkinson, W.E., Glanville, S.H., McConnell, F.M., Scott, H.S., Penninger, J.M., Jenkinson, E.J., . (2007b). RANK signals from CD4(+)3(-) inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J Exp Med 204, 1267-1272 .10.1084/jem.20062497
[101] Saade, M., Irla, M., Yammine, M., Boulanger, N., Victorero, G., Vincentelli, R., Penninger, J.M., Hollander, G.A., Chauvet, S., and Nguyen, C. (2010). Spatial (Tbata) expression in mature medullary thymic epithelial cells. Eur J Immunol 40, 530-538 .10.1002/eji.200939605
[102] 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., . (2008). The lymphotoxin pathway regulates Aire-independent expression of ectopic genes and chemokines in thymic stromal cells. J Immunol 180, 5384-5392 .
[103] Senoo, M., Pinto, F., Crum, C.P., and McKeon, F. (2007). p63 Is essential for the proliferative potential of stem cells in stratifi ed epithelia. Cell 129, 523-536 .10.1016/j.cell.2007.02.045
[104] 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 .10.4049/jimmunol.0990018
[105] Sitnik, K.M., Kotarsky, K., White, A.J., Jenkinson, W.E., Anderson, G., and Agace, W.W. (2012). Mesenchymal cells regulate retinoic acid receptor-dependent cortical thymic epithelial cell homeostasis. J Immunol 188, 4801-4809 .10.4049/jimmunol.1200358
[106] Su, D., Ellis, S., Napier, A., Lee, K., and Manley, N.R. (2001). Hoxa3 and pax1 regulate epithelial cell death and proliferation during thymus and parathyroid organogenesis. Dev Biol 236, 316-329 .10.1006/dbio.2001.0342
[107] Su, D.M., Navarre, S., Oh, W.J., Condie, B.G., and Manley, N.R. (2003). A domain of Foxn1 required for crosstalk-dependent thymic epithelial cell differentiation. Nat Immunol 4, 1128-1135 .10.1038/ni983
[108] Suniara, R.K., Jenkinson, E.J., and Owen, J.J. (2000). An essential role for thymic mesenchyme in early T cell development. J Exp Med 191, 1051-1056 .10.1084/jem.191.6.1051
[109] Takahama, Y., Takada, K., Murata, S., and Tanaka, K. (2012). beta5tcontaining thymoproteasome: specifi c expression in thymic cortical epithelial cells and role in positive selection of CD8+ T cells. Curr Opin Immunol 24, 92-98 .10.1016/j.coi.2012.01.006
[110] Talaber, G., Kvell, K., Varecza, Z., Boldizsar, F., Parnell, S.M., Jenkinson, E.J., Anderson, G., Berki, T., and Pongracz, J.E. (2011). Wnt- 4 protects thymic epithelial cells against dexamethasone-induced senescence. Rejuvenation Res 14, 241-248 .10.1089/rej.2010.1110
[111] Tsai, P.T., Lee, R.A., and Wu, H. (2003). BMP4 acts upstream of FGF in modulating thymic stroma and regulating thymopoiesis. Blood 102, 3947-3953 .10.1182/blood-2003-05-1657
[112] Varecza, Z., Kvell, K., Talaber, G., Miskei, G., Csongei, V., Bartis, D., Anderson, G., Jenkinson, E.J., and Pongracz, J.E. (2011). Multiple suppression pathways of canonical Wnt signalling control thymic epithelial senescence. Mech Ageing Dev 132, 249-256 .10.1016/j.mad.2011.04.007
[113] Venanzi, E.S., Gray, D.H., Benoist, C., and Mathis, D. (2007). Lymphotoxin pathway and Aire infl uences on thymic medullary epithelial cells are unconnected. J Immunol 179, 5693-5700 .
[114] Viret, C., Leung-Theung-Long, S., Serre, L., Lamare, C., Vignali, D.A., Malissen, B., Carrier, A., and Guerder, S. (2011). Thymus-specifi c serine protease controls autoreactive CD4 T cell development and autoimmune diabetes in mice. J Clin Invest 121, 1810-1821 .10.1172/JCI43314
[115] Wang, X., Laan, M., Bichele, R., Kisand, K., Scott, H.S., and Peterson, P. (2012). Post-Aire maturation of thymic medullary epithelial cells involves selective expression of keratinocyte-specifi c autoantigens. Front Immunol 3, 19.10.3389/fimmu.2012.00019
[116] Weber, S., Niessen, M.T., Prox, J., Lullmann-Rauch, R., Schmitz, A., Schwanbeck, R., Blobel, C.P., Jorissen, E., de Strooper, B., Niessen, C.M., . (2011). The disintegrin/metalloproteinase Adam10 is essential for epidermal integrity and Notch-mediated signaling. Development 138, 495-505 .10.1242/dev.055210
[117] Weih, F., Carrasco, D., Durham, S.K., Barton, D.S., Rizzo, C.A., Ryseck, R.P., Lira, S.A., and Bravo, R. (1995). Multiorgan infl ammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell 80, 331-340 .10.1016/0092-8674(95)90416-6
[118] Wendling, O., Dennefeld, C., Chambon, P., and Mark, M. (2000). Retinoid signaling is essential for patterning the endoderm of the third and fourth pharyngeal arches. Development 127, 1553-1562 .
[119] West, K.P., Jr., Howard, G.R., and Sommer, A. (1989). Vitamin A and infection: public health implications. Annu Rev Nutr 9, 63-86 .10.1146/annurev.nu.09.070189.000431
[120] White, A.J., Nakamura, K., Jenkinson, W.E., Saini, M., Sinclair, C., Seddon, B., Narendran, P., Pfeffer, K., Nitta, T., Takahama, Y., . (2010). Lymphotoxin signals from positively selected thymocytes regulate the terminal differentiation of medullary thymic epithelial cells. J Immunol 185, 4769-4776 .10.4049/jimmunol.1002151
[121] Wodarz, A., and Nusse, R. (1998). Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol 14, 59-88 .10.1146/annurev.cellbio.14.1.59
[122] Xia, J., Wang, H., Guo, J., Zhang, Z., Coder, B., and Su, D.M. (2012). Age-related disruption of steady-state thymic medulla provokes autoimmune phenotype via perturbing negative selection. Aging Dis 3, 248-259 .
[123] Yano, M., Kuroda, N., Han, H., Meguro-Horike, M., Nishikawa, Y., Kiyonari, H., Maemura, K., Yanagawa, Y., Obata, K., Takahashi, S., . (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 .10.1084/jem.20080046
[124] 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 .10.1074/jbc.M606705200
[125] Zhang, L., Sun, L., and Zhao, Y. (2007). Thymic epithelial progenitor cells and thymus regeneration: an update. Cell Res 17, 50-55 .10.1038/sj.cr.7310114
[126] 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 .10.1016/j.it.2010.06.005
[127] 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 .10.1172/JCI28326
[128] Zhu, M., and Fu, Y. (2010). The complicated role of NF-kappaB in T-cell selection. Cell Mol Immunol 7, 89-93 .10.1038/cmi.2009.112
[129] Zook, E.C., Krishack, P.A., Zhang, S., Zeleznik-Le, N.J., Firulli, A.B., Witte, P.L., and Le, P.T. (2011). Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells. Blood 118, 5723-5731 .10.1182/blood-2011-03-342097
[130] Zuklys, S., Mayer, C.E., Zhanybekova, S., Stefanski, H.E., Nusspaumer, G., Gill, J., Barthlott, T., Chappaz, S., Nitta, T., Dooley, J., . (2012). MicroRNAs control the maintenance of thymic epithelia and their competence for T lineage commitment and thymocyte selection. J Immunol 189, 3894-3904 .10.4049/jimmunol.1200783
AI Summary AI Mindmap
PDF(443 KB)

Accesses

Citations

Detail

Sections
Recommended

/