Structure and function of the thymic microenvironment

Frontiers in Bioscience

Volumn 16, Issue 7, 2011, Pages 2461-2477

  Manley, Nancy Ruth ^a,e   Richie, Ellen Rothman ^b   Blackburn, Catherine Clare ^c   Condie, Brian Gene ^a   Sage, Julien ^d  

^a University of Georgia ^*  (United States)

^b UNIVERSITY OF TEXAS   (United States)

^c UNIVERSITY OF EDINBURGH   (United Kingdom)

^d STANFORD UNIVERSITY   (United States)

^e UNIVERSITY OF GEORGIA   (United States)

Author keywords

Cell Cycle; Foxn1; Microenvironment; Niche; Progenitor cells; Review; Stem cells; T cells; Thymic epithelium; Thymus

Indexed keywords

ANIMAL; CELL COMMUNICATION; CELL CYCLE; CELL DIFFERENTIATION; CELL PROLIFERATION; CYTOLOGY; EPITHELIAL MESENCHYMAL TRANSITION; EPITHELIUM CELL; GROWTH, DEVELOPMENT AND AGING; HISTOLOGY; HUMAN; NEURAL CREST; PHYSIOLOGY; REVIEW; STEM CELL; T LYMPHOCYTE; THYMUS; TRANSLATIONAL RESEARCH;

ANIMALS; CELL COMMUNICATION; CELL CYCLE; CELL DIFFERENTIATION; CELL PROLIFERATION; EPITHELIAL CELLS; EPITHELIAL-MESENCHYMAL TRANSITION; HUMANS; NEURAL CREST; STEM CELLS; T-LYMPHOCYTES; THYMUS GLAND; TRANSLATIONAL RESEARCH;

EID: 79959567594     PISSN: 27686701     EISSN: 27686698     Source Type: Journal    
DOI: 10.2741/3866     Document Type: Article

References (142)

1. J. Gordon, V. A. Wilson, N. F. Blair, J. Sheridan, A. Farley, L. Wilson, N. R. Manley and C. C. Blackburn: Functional evidence for a single endodermal origin for the thymic epithelium. Nat Immunol, 5(5), 546-53 (2004) (Pubitemid 38660468)
2. B. Adkins: T-cell function in newborn mice and humans. Immunol Today, 20(7), 330-5 (1999) (Pubitemid 29331539)
3. B. Adkins: Peripheral CD4+ lymphocytes derived from fetal versus adult thymic precursors differ phenotypically and functionally. J Immunol, 171(10), 5157-64 (2003) (Pubitemid 37432799)
4. B. Min, R. McHugh, G. D. Sempowski, C. Mackall, G. Foucras and W. E. Paul: Neonates support lymphopeniainduced proliferation. Immunity, 18(1), 131-40 (2003)
5. H. Min, E. Montecino-Rodriguez and K. Dorshkind: Reduction in the developmental potential of intrathymic T cell progenitors with age. J Immunol, 173(1), 245-50 (2004) (Pubitemid 38797348)
6. H. Min, E. Montecino-Rodriguez and K. Dorshkind: Reassessing the role of growth hormone and sex steroids in thymic involution. Clin Immunol, 118(1), 117-23 (2006) (Pubitemid 43012054)
7. N. R. Manley: Thymus organogenesis and molecular mechanisms of thymic epithelial cell differentiation. Semin Immunol, 12(5), 421-8 (2000)
8. M. A. Ritter and R. L. Boyd: Development in the thymus: it takes two to tango. Immunol Today, 14(9), 462-9 (1993) (Pubitemid 23271745)
9. E. F. Lind, S. E. Prockop, H. E. Porritt and H. T. Petrie: Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development. J Exp Med, 194(2), 127-34 (2001) (Pubitemid 32673345)
10. H. T. Petrie, M. Tourigny, D. B. Burtrum and F. Livak: Precursor thymocyte proliferation and differentiation are controlled by signals unrelated to the pre-TCR. J Immunol, 165(6), 3094-8 (2000)
11. W. van Ewijk, E. W. Shores and A. Singer: Crosstalk in the mouse thymus. Immunol Today, 15, 214-217 (1994) (Pubitemid 24137974)
12. G. Anderson and E. J. Jenkinson: Lymphostromal interactions in thymic development and function. Nat Rev Immunol, 1(1), 31-40 (2001) (Pubitemid 33741973)
13. A. M. Gallegos and M. J. Bevan: Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J Exp Med, 200(8), 1039-49 (2004) (Pubitemid 39431128)
14. C. Koble and B. Kyewski: The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J Exp Med, 206(7), 1505-13 (2009)
15. C. D. Surh and J. Sprent: T-cell apoptosis detected in situ during positive and negative selection in the thymus [see comments]. Nature, 372(6501), 100-3 (1994) (Pubitemid 24339491)
16. U. Koch, E. Fiorini, R. Benedito, V. Besseyrias, K. Schuster-Gossler, M. Pierres, N. R. Manley, A. Duarte, H. R. Macdonald and F. Radtke: Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. J Exp Med, 205(11), 2515-23 (2008)
17. G. Anderson, J. Pongracz, S. Parnell and E. J. Jenkinson: Notch ligand-bearing thymic epithelial cells initiate and sustain Notch signaling in thymocytes independently of T cell receptor signaling. Eur J Immunol, 31(11), 3349-54 (2001) (Pubitemid 33100527)
18. K. Hozumi, C. Mailhos, N. Negishi, K. Hirano, T. Yahata, K. Ando, S. Zuklys, G. A. Hollander, D. T. Shima and S. Habu: Delta-like 4 is indispensable in thymic environment specific for T cell development. J Exp Med, 205(11), 2507-13 (2008)
19. B. F. Haynes, G. D. Sempowski, A. F. Wells and L. P. Hale: The human thymus during aging. Immunol Res, 22(2-3), 253-61 (2000) (Pubitemid 32382238)
20. G. D. Sempowski, L. P. Hale, J. S. Sundy, J. M. Massey, R. A. Koup, D. C. Douek, D. D. Patel and B. F. Haynes: Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy. J Immunol, 164(4), 2180-7 (2000) (Pubitemid 30108777)
21. G. G. Steinmann: Changes in the human thymus during aging. Curr Top Pathol, 75, 43-88 (1986)
22. Y. H. Youm, H. Yang, Y. Sun, R. G. Smith, N. R. Manley, B. Vandanmagsar and V. D. Dixit: Deficient ghrelin receptor-mediated signaling compromises thymic stromal cell microenvironment by accelerating thymic adiposity. J Biol Chem, 284(11), 7068-77 (2009)
23. T. K. Starr, S. C. Jameson and K. A. Hogquist: Positive and negative selection of T cells. Annu Rev Immunol, 21, 139-76 (2003) (Pubitemid 37174529)
24. K. A. Hogquist, T. A. Baldwin and S. C. Jameson: Central tolerance: learning self-control in the thymus. Nat Rev Immunol, 5(10), 772-82 (2005) (Pubitemid 41400851)
25. L. Klein, M. Hinterberger, G. Wirnsberger and B. Kyewski: Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol, 9(12), 833-44 (2009)
26. C. Ohnmacht, A. Pullner, S. B. King, I. Drexler, S. Meier, T. Brocker and D. Voehringer: Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J Exp Med, 206(3), 549-59 (2009)
27. M. S. Anderson, E. S. Venanzi, L. Klein, Z. Chen, S. P. Berzins, S. J. Turley, H. von Boehmer, R. Bronson, A. Dierich, C. Benoist and D. Mathis: Projection of an immunological self shadow within the thymus by the aire protein. Science, 298(5597), 1395-401 (2002) (Pubitemid 35346134)
28. M. Kronenberg and A. Rudensky: Regulation of immunity by self-reactive T cells. Nature, 435(7042), 598-604 (2005) (Pubitemid 40825499)
29. M. Hinterberger, M. Aichinger, O. P. da Costa, D. Voehringer, R. Hoffmann and L. Klein: Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance. Nat Immunol, 11(6), 512-9 (2010)
30. K. Aschenbrenner, L. M. D'Cruz, E. H. Vollmann, M. Hinterberger, J. Emmerich, L. K. Swee, A. Rolink and L. Klein: Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol, 8(4), 351-8 (2007) (Pubitemid 46745410)
31. G. Anderson, W. E. Jenkinson, T. Jones, S. M. Parnell, F. A. Kinsella, A. J. White, J. E. Pongrac'z, S. W. Rossi and E. J. Jenkinson: Establishment and functioning of intrathymic microenvironments. Immunol Rev, 209, 10-27 (2006)
32. J. Gill, M. Malin, J. Sutherland, D. Gray, G. Hollander and R. Boyd: Thymic generation and regeneration. Immunol Rev, 195, 28-50 (2003) (Pubitemid 37153451)
33. D. B. Klug, C. Carter, E. Crouch, D. Roop, C. J. Conti and E. R. Richie: Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc Natl Acad Sci U S A, 95(20), 11822-7 (1998) (Pubitemid 28460498)
34. G. A. Hollander, B. Wang, A. Nichogiannopoulou, P. P. Platenburg, W. van Ewijk, S. J. Burakoff, J.-C. Gutierrez-Ramos and C. Terhorst: Developmental control point in the induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature, 373, 350-353 (1995)
35. W. van Ewijk, G. Hollander, C. Terhorst and B. Wang: Stepwise development of thymic microenvironments in vivo is regulated by thymocyte subsets. Development, 127(8), 1583-91. (2000) (Pubitemid 30234916)
36. W. van Ewijk, H. Kawamoto, W. T. Germeraad and Y. Katsura: Developing thymocytes organize thymic microenvironments. Curr Top Microbiol Immunol, 251, 125-32 (2000)
37. M. Zamisch, B. Moore-Scott, D. M. Su, P. J. Lucas, N. Manley and E. R. Richie: Ontogeny and regulation of IL-7-expressing thymic epithelial cells. J Immunol, 174(1), 60-7 (2005) (Pubitemid 40007392)
38. E. W. Shores, W. Van Ewijk and A. Singer: Maturation of medullary thymic epithelium requires thymocytes expressing fully assembled CD3-TCR complexes. Int Immunol, 6(9), 1393-402 (1994) (Pubitemid 24296855)
39. C. D. Surh, B. Ernst and J. Sprent: Growth of epithelial cells in the thymic medulla is under the control of mature T cells. J Exp Med, 176(2), 611-6 (1992)
40. S. W. Rossi, M. Y. Kim, A. Leibbrandt, S. M. Parnell, W. E. Jenkinson, S. H. Glanville, F. M. McConnell, H. S. Scott, J. M. Penninger, E. J. Jenkinson, P. J. Lane and G. Anderson: RANK signals from CD4(+)3(-) inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J Exp Med, 204(6), 1267-72 (2007) (Pubitemid 46919863)
41. T. Akiyama, Y. Shimo, H. Yanai, J. Qin, D. Ohshima, Y. Maruyama, Y. Asaumi, J. Kitazawa, H. Takayanagi, J. M. Penninger, M. Matsumoto, T. Nitta, Y. Takahama and J. Inoue: The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity, 29(3), 423-37 (2008)
42. Y. Hikosaka, T. Nitta, I. Ohigashi, K. Yano, N. Ishimaru, Y. Hayashi, M. Matsumoto, K. Matsuo, J. M. Penninger, H. Takayanagi, Y. Yokota, H. Yamada, Y. Yoshikai, J. Inoue, T. Akiyama and Y. Takahama: The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity, 29(3), 438-50 (2008)
43. T. Boehm, S. Scheu, K. Pfeffer and C. C. Bleul: Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTbetaR. J Exp Med, 198(5), 757-69 (2003) (Pubitemid 37087775)
44. M. Irla, S. Hugues, J. Gill, T. Nitta, Y. Hikosaka, I. R. Williams, F. X. Hubert, H. S. Scott, Y. Takahama, G. A. Hollander and W. Reith: Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity. Immunity, 29(3), 451-63 (2008)
45. R. Auerbach: Morphogenetic interactions in the development of the mouse thymus gland. Dev. Biol., 2, 271-284 (1960)
46. D. E. Bockman and M. L. Kirby: Dependence of thymus development on derivatives of the neural crest. Science, 223, 498-500 (1984) (Pubitemid 14221398)
47. N. M. Le Douarin and F. V. Jotereau: Tracing of cells of the avian thymus through embryonic life in interspecific chimeras. J Exp Med, 142(1), 17-40 (1975)
48. A. V. Griffith, K. Cardenas, C. Carter, J. Gordon, A. Iberg, K. Engleka, J. A. Epstein, N. R. Manley and E. R. Richie: Increased thymus- and decreased parathyroid-fated organ domains in Splotch mutant embryos. Dev Biol, 327(1), 216-27 (2009)
49. J. Gordon, S. R. Patel, Y. Mishina and N. R. Manley: Evidence for an early role for BMP4 signaling in thymus and parathyroid morphogenesis. Dev Biol, 339(1), 141-54 (2010)
50. K. E. Foster, J. Gordon, K. Cardenas, H. Veiga-Fernandes, T. Makinen, E. Grigorieva, D. G. Wilkinson, C. C. Blackburn, E. Richie, N. R. Manley, R. H. Adams, D. Kioussis and M. C. Coles: EphB-ephrin-B2 interactions are required for thymus migration during organogenesis. Proc Natl Acad Sci U S A, 107(30), 13414-9 (2010)
51. P. H. Crossley, G. Minowada, C. A. MacArther and G. R. Martin: Roles for FGF8 in the induction, initiation andmaintenance of chick limb development. Cell, 84, 127-136 (1996) (Pubitemid 26031467)
52. A. M. Moon and M. R. Capecchi: Fgf8 is required for outgrowth and patterning of the limbs. Nat Genet, 26(4), 455-9 (2000)
53. D. U. Frank, L. K. Fotheringham, J. A. Brewer, L. J. Muglia, M. Tristani-Firouzi, M. R. Capecchi and A. M. Moon: An Fgf8 mouse mutant phenocopies human 22q11 deletion syndrome. Development, 129(19), 4591-603 (2002) (Pubitemid 35203740)
54. M. Erickson, S. Morkowski, S. Lehar, G. Gillard, C. Beers, J. Dooley, J. S. Rubin, A. Rudensky and A. G. Farr: Regulation of thymic epithelium by keratinocyte growth factor. Blood, 100(9), 3269-78 (2002) (Pubitemid 35217077)
55. W. E. Jenkinson, E. J. Jenkinson and G. Anderson: Differential requirement for mesenchyme in the proliferation and maturation of thymic epithelial progenitors. J Exp Med, 198(2), 325-32 (2003) (Pubitemid 36987857)
56. J. M. Revest, R. K. Suniara, K. Kerr, J. J. Owen and C. Dickson: Development of the thymus requires signaling through the fibroblast growth factor receptor r2-iiib. J Immunol, 167(4), 1954-61 (2001) (Pubitemid 32747500)
57. W. E. Jenkinson, S. W. Rossi, S. M. Parnell, E. J.Jenkinson and G. Anderson: PDGFR{alpha}-expressing mesenchyme regulates thymus growth and the availability of intrathymic niches. Blood, 109(3), 954-60 (2007) (Pubitemid 46220639)
58. G. Balciunaite, M. P. Keller, E. Balciunaite, L. Piali, S. Zuklys, Y. D. Mathieu, J. Gill, R. Boyd, D. J. Sussman and G. A. Hollander: Wnt glycoproteins regulate the expression of FoxN1, the gene defective in nude mice. Nat Immunol, 3(11), 1102-8 (2002) (Pubitemid 35363665)
59. C. C. Bleul and T. Boehm: BMP signaling is required for normal thymus development. J Immunol, 175(8), 5213-21 (2005) (Pubitemid 41456406)
60. D. A. Sultana, S. Tomita, M. Hamada, Y. Iwanaga, Y. Kitahama, N. V. Khang, S. Hirai, I. Ohigashi, S. Nitta, T. Amagai, S. Takahashi and Y. Takahama: Gene expression profile of the third pharyngeal pouch reveals role of mesenchymal MafB in embryonic thymus development. Blood, 113(13), 2976-87 (2009)
61. C. Liu, T. Ueno, S. Kuse, F. Saito, T. Nitta, L. Piali, H. Nakano, T. Kakiuchi, M. Lipp, G. A. Hollander and Y. Takahama: The role of CCL21 in recruitment of Tprecursor cells to fetal thymi. Blood, 105(1), 31-9 (2005) (Pubitemid 40053060)
62. G. Anderson, K. L. Anderson, E. Z. Tchilian, J. J. Owen and E. J. Jenkinson: Fibroblast dependency during early thymocyte development maps to the CD25+CD44+ stage and involves interactions with fibroblast matrix molecules. Eur J Immunol, 27(5), 1200-6 (1997) (Pubitemid 27197224)
63. D. H. Gray, N. Seach, T. Ueno, M. K. Milton, A. Liston, A. M. Lew, C. C. Goodnow and R. L. Boyd: Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood, 108(12), 3777-85 (2006) (Pubitemid 44864559)
64. C. Liu, F. Saito, Z. Liu, Y. Lei, S. Uehara, P. Love, M. Lipp, S. Kondo, N. Manley and Y. Takahama: Coordination between CCR7- and CCR9-mediated chemokine signals in prevascular fetal thymus colonization. Blood, 108(8), 2531-9 (2006)
65. E. Ladi, X. Yin, T. Chtanova and E. A. Robey: Thymic microenvironments for T cell differentiation and selection. Nat Immunol, 7(4), 338-43 (2006)
66. K. Mori, M. Itoi, N. Tsukamoto and T. Amagai: Foxn1 is essential for vascularization of the murine thymus anlage. Cell Immunol, 260(2), 66-9 (2010)
67. M. Anderson, S. K. Anderson and A. G. Farr: Thymic vasculature: organizer of the medullary epithelial compartment? Int Immunol, 12(7), 1105-10 (2000) (Pubitemid 30599361)
68. K. Foster, J. Sheridan, H. Veiga-Fernandes, K. Roderick, V. Pachnis, R. Adams, C. Blackburn, D. Kioussis and M. Coles: Contribution of neural crest-derived cells in the embryonic and adult thymus. J Immunol, 180(5), 3183-9 (2008)
69. S. M. Muller, G. Terszowski, C. Blum, C. Haller, V. Anquez, S. Kuschert, P. Carmeliet, H. G. Augustin and H. R. Rodewald: Gene targeting of VEGF-A in thymus epithelium disrupts thymus blood vessel architecture. Proc Natl Acad Sci U S A, 102(30), 10587-92 (2005) (Pubitemid 41061598)
70. M. A. Zachariah and J. G. Cyster: Neural crest-derived pericytes promote egress of mature thymocytes at the corticomedullary junction. Science, 328(5982), 1129-35 (2010)
71. A. R. Cuddihy, S. Ge, J. Zhu, J. Jang, A. Chidgey, G. Thurston, R. Boyd and G. M. Crooks: VEGF-mediated cross-talk within the neonatal murine thymus. Blood, 113(12), 2723-31 (2009)
72. R. M. Seaberg and D. van der Kooy: Stem and progenitor cells: the premature desertion of rigorous definitions. Trends Neurosci, 26(3), 125-31 (2003) (Pubitemid 36183673)
73. K. A. Moore and I. R. Lemischka: Stem cells and their niches. Science, 311(5769), 1880-5 (2006)
74. L. Gambardella and Y. Barrandon: The multifaceted adult epidermal stem cell. Curr Opin Cell Biol, 15(6), 771-7 (2003) (Pubitemid 37487971)
75. J. Cairns: Somatic stem cells and the kinetics of mutagenesis and carcinogenesis. Proc Natl Acad Sci U S A, 99(16), 10567-70 (2002)
76. H. J. Snippert, L. G. van der Flier, T. Sato, J. H. van Es, M. van den Born, C. Kroon-Veenboer, N. Barker, A. M. Klein, J. van Rheenen, B. D. Simons and H. Clevers: Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell, 143(1), 134-44 (2010)
77. X. Wang, M. Foster, M. Al-Dhalimy, E. Lagasse, M. Finegold and M. Grompe: The origin and liver repopulating capacity of murine oval cells. Proc Natl Acad Sci U S A, 100 Suppl 1, 11881-8 (2003) (Pubitemid 37205899)
78. Y. Dor, J. Brown, O. I. Martinez and D. A. Melton: Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature, 429(6987), 41-6 (2004) (Pubitemid 38620543)
79. X. Xu, J. D'Hoker, G. Stange, S. Bonne, N. De Leu, X. Xiao, M. Van De Casteele, G. Mellitzer, Z. Ling, D. Pipeleers, L. Bouwens, R. Scharfmann, G. Gradwohl and H. Heimberg: beta Cells Can Be Generated from Endogenous Progenitors in Injured Adult Mouse Pancreas. Cell, 132(2), 197-207 (2008) (Pubitemid 351181232)
80. A. Smith: A glossary for stem-cell biology. Nature, 441, 1060 (2006)
81. C. C. Blackburn, C. L. Augustine, R. Li, R. P. Harvey, M. A. Malin, R. L. Boyd, J. F. Miller and G. Morahan: The nu gene acts cell-autonomously and is required for differentiation of thymic epithelial progenitors. Proc. Natl. Acad. Sci. USA, 93(12), 5742-6 (1996) (Pubitemid 26190750)
82. A. R. Bennett, A. Farley, N. F. Blair, J. Gordon, L. Sharp and C. C. Blackburn: Identification and characterization of thymic epithelial progenitor cells. Immunity, 16(6), 803-14 (2002) (Pubitemid 34786479)
83. M. G. Depreter, N. F. Blair, T. L. Gaskell, C. S. Nowell, K. Davern, A. Pagliocca, F. H. Stenhouse, A. M. Farley, A. Fraser, J. Vrana, K. Robertson, G. Morahan, S. R. Tomlinson and C. C. Blackburn: Identification of Plet-1 as a specific marker of early thymic epithelial progenitor cells. Proc Natl Acad Sci U S A, 105(3), 961-6 (2008) (Pubitemid 351282064)
84. B. A. Moore-Scott, R. Opoka, S. C. Lin, J. J. Kordich and J. M. Wells: Identification of molecular markers that are expressed in discrete anterior-posterior domains of the endoderm from the gastrula stage to mid-gestation. Dev Dyn, 236(7), 1997-2003 (2007) (Pubitemid 47076028)
85. J. Gill, M. Malin, G. A. Hollander and R. Boyd: Generation of a complete thymic microenvironment by MTS24(+) thymic epithelial cells. Nat Immunol, 3(7), 635-42 (2002) (Pubitemid 34752472)
86. S. W. Rossi, A. P. Chidgey, S. M. Parnell, W. E. Jenkinson, H. S. Scott, R. L. Boyd, E. J. Jenkinson and G. Anderson: Redefining epithelial progenitor potential in the developing thymus. Eur J Immunol, 37(9), 2411-8 (2007) (Pubitemid 47423612)
87. C. C. Bleul, T. Corbeaux, A. Reuter, P. Fisch, J. S. Monting and T. Boehm: Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature, 441(7096), 992-6 (2006) (Pubitemid 43980354)
88. S. W. Rossi, W. E. Jenkinson, G. Anderson and E. J. Jenkinson: Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature, 441(7096), 988-91 (2006) (Pubitemid 43980353)
89. H. R. Rodewald, S. Paul, C. Haller, H. Bluethmann and C. Blum: Thymus medulla consisting of epithelial islets each derived from a single progenitor. Nature, 414(6865), 763-8 (2001) (Pubitemid 34000775)
90. Y. Hamazaki, H. Fujita, T. Kobayashi, Y. Choi, H. S. Scott, M. Matsumoto and N. Minato: Medullary thymic epithelial cells expressing Aire represent a unique lineage derived from cells expressing claudin. Nat Immunol, 8(3), 304-11 (2007) (Pubitemid 46745380)
91. S. Shakib, G. E. Desanti, W. E. Jenkinson, S. M. Parnell, E. J. Jenkinson and G. Anderson: Checkpoints in the development of thymic cortical epithelial cells. J Immunol, 182(1), 130-7 (2009)
92. M. Schluep, N. Willcox, M. A. Ritter, J. Newsom-Davis, M. Larche and A. N. Brown: Myasthenia gravis thymus: clinical, histological and culture correlations. J Autoimmun, 1(5), 445-67 (1988)
93. C. C. Blackburn, N. R. Manley, D. B. Palmer, R. L. Boyd, G. Anderson and M. A. Ritter: One for all and all for one: thymic epithelial stem cells and regeneration. Trends Immunol, 23(8), 391-5 (2002) (Pubitemid 34804634)
94. D. Min, A. Panoskaltsis-Mortari, O. M. Kuro, G. A. Hollander, B. R. Blazar and K. I. Weinberg: Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood, 109(6), 2529-37 (2007) (Pubitemid 46425898)
95. X. Xu, J. D'Hoker, G. Stangé, S. Bonné, N. De Leu, X. L. Xiao, M. Van de Casteele, G. Mellitzer, Z. Ling, D. Pipeleers, L. Bouwens, R. Scharfmann, G. Gradwohl and H. Heimberg: Beta cells can be generated from endogenours progenitors in injured adult mouse pancreas. Cell, 132, 197-207 (2008) (Pubitemid 351181232)
96. M. Senoo, F. Pinto, C. P. Crum and F. McKeon: p63 Is essential for the proliferative potential of stem cells in stratified epithelia. Cell, 129(3), 523-36 (2007) (Pubitemid 46660965)
97. P. Bonfanti, S. Claudinot, A. W. Amici, A. Farley, C. C. Blackburn and Y. Barrandon: Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells. Nature, 466(7309), 978-82 (2010)
98. T. Corbeaux, I. Hess, J. B. Swann, B. Kanzler, A. Haas- Assenbaum and T. Boehm: Thymopoiesis in mice depends on a Foxn1-positive thymic epithelial cell lineage. Proc Natl Acad Sci U S A, 107(38), 16613-8 (2010)
99. K. H. Kaestner, W. Knochel and D. E. Martinez: Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev, 14(2), 142-6 (2000) (Pubitemid 30070978)
100. M. Nehls, D. Pfeifer, M. Schorpp, H. Hedrich and T. Boehm: New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature, 372(6501), 103-7 (1994) (Pubitemid 24339492)
101. M. Nehls, B. Kyewski, M. Messerle, R. Waldschütz, K. Schüddekopf, A. J. Smith and T. Boehm: Two genetically separable steps in the differentiation of thymic epithelium. Science, 272(5263), 886-9 (1996) (Pubitemid 26154594)
102. N. R. Manley and B. G. Condie: Transcriptional regulation of thymus organogenesis and thymic epithelial cell differentiation. Prog Mol Biol Transl Sci, 92, 103-20 (2010)
103. M. Itoi, N. Tsukamoto and T. Amagai: Expression of Dll4 and CCL25 in Foxn1-negative epithelial cells in the post-natal thymus. Int Immunol, 19(2), 127-32 (2007) (Pubitemid 46179007)
104. L. Chen, S. Xiao and N. R. Manley: Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner. Blood, 113(3), 567-74 (2009)
105. J. Gordon, S. Xiao, B. Hughes, 3rd, D. M. Su, S. P. Navarre, B. G. Condie and N. R. Manley: Specific expression of lacZ and cre recombinase in fetal thymic epithelial cells by multiplex gene targeting at the Foxn1 locus. BMC Dev Biol, 7(1), 69 (2007)
106. A. Liston, A. G. Farr, Z. Chen, C. Benoist, D. Mathis, N. R. Manley and A. Y. Rudensky: Lack of Foxp3 function and expression in the thymic epithelium. J Exp Med, 204(3), 475-80 (2007) (Pubitemid 46457071)
107. E. Vroegindeweij, S. Crobach, M. Itoi, R. Satoh, S. Zuklys, C. Happe, W. T. Germeraad, J. J. Cornelissen, T. Cupedo, G. A. Hollander, H. Kawamoto and W. van Ewijk: Thymic cysts originate from Foxn1 positive thymic medullary epithelium. Mol Immunol, 47(5), 1106-13 (2010)
108. L. Cheng, J. Guo, L. Sun, J. Fu, P. F. Barnes, D. Metzger, P. Chambon, R. G. Oshima, T. Amagai and D. M. Su: Postnatal tissue-specific disruption of transcription factor FoxN1 triggers acute thymic atrophy. J Biol Chem, 285(8), 5836-47 (2010)
109. L. Sun, J. Guo, R. Brown, T. Amagai, Y. Zhao and D. M. Su: Declining expression of a single epithelial cellautonomous gene accelerates age-related thymic involution. Aging Cell, 9(3), 347-57 (2010)
110. C. L. Ortman, K. A. Dittmar, P. L. Witte and P. T. Le: Molecular characterization of the mouse involuted thymus: aberrations in expression of transcription regulators in thymocyte and epithelial compartments. Int Immunol, 14(7), 813-22 (2002) (Pubitemid 34814642)
111. A. I. Robles, F. Larcher, R. B. Whalin, R. Murillas, E. Richie, I. B. Gimenez-Conti, J. L. Jorcano and C. J. Conti: Expression of cyclin D1 in epithelial tissues of transgenic mice results in epidermal hyperproliferation and severe thymic hyperplasia. Proc Natl Acad Sci U S A, 93(15), 7634-8 (1996) (Pubitemid 26277088)
112. R. Sotillo, P. Dubus, J. Martin, E. de la Cueva, S. Ortega, M. Malumbres and M. Barbacid: Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4 inhibitors. Embo J, 20(23), 6637-47 (2001) (Pubitemid 33134194)
113. S. G. Rane, S. C. Cosenza, R. V. Mettus and E. P. Reddy: Germ line transmission of the Cdk4(R24C) mutation facilitates tumorigenesis and escape from cellular senescence. Mol Cell Biol, 22(2), 644-56 (2002) (Pubitemid 34027508)
114. B. Scheijen, M. Bronk, T. van der Meer, D. De Jong and R. Bernards: High incidence of thymic epithelial tumors in E2F2 transgenic mice. J Biol Chem, 279(11), 10476-83 (2004) (Pubitemid 38372657)
115. A. M. Pierce, S. M. Fisher, C. J. Conti and D. G. Johnson: Deregulated expression of E2F1 induces hyperplasia and cooperates with ras in skin tumor development. Oncogene, 16(10), 1267-76 (1998) (Pubitemid 28138199)
116. A. Iglesias, M. Murga, U. Laresgoiti, A. Skoudy, I. Bernales, A. Fullaondo, B. Moreno, J. Lloreta, S. J. Field, F. X. Real and A. M. Zubiaga: Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice. J Clin Invest, 113(10), 1398-407 (2004) (Pubitemid 39071695)
117. J. Moll, H. Eibel, F. Botteri, G. Sansig, C. Regnier and H. van der Putten: Transgenes encoding mutant simian virus 40 large T antigens unmask phenotypic and functional constraints in thymic epithelial cells. Oncogene, 7(11), 2175-87 (1992)
118. N. K. Kim, S. H. Lee, K. Y. Cha and J. S. Seo: Tissuespecific expression and activation of N-methylpurine-DNA glycosylase in thymic carcinomas of transgenic mice expressing the SV40 large T-antigen gene. Mol Cells, 8(4), 383-7 (1998) (Pubitemid 128676295)
119. L. Carraresi, S. A. Tripodi, L. C. Mulder, S. Bertini, S. Nuti, K. Schuerfeld, M. Cintorino, G. Bensi, M. Rossini and M. Mora: Thymic hyperplasia and lung carcinomas in a line of mice transgenic for keratin 5-driven HPV16 E6/E7 oncogenes. Oncogene, 20(56), 8148-53 (2001) (Pubitemid 34028340)
120. K. M. Malcolm, J. Gill, G. R. Leggatt, R. Boyd, P. Lambert and I. H. Frazer: Expression of the HPV16E7 oncoprotein by thymic epithelium is accompanied by disrupted T cell maturation and a failure of the thymus to involute with age. Clin Dev Immunol, 10(2-4), 91-103 (2003) (Pubitemid 38089399)
121. D. S. Franklin, V. L. Godfrey, H. Lee, G. I. Kovalev, R. Schoonhoven, S. Chen-Kiang, L. Su and Y. Xiong: CDK inhibitors p18(INK4c) and p27(Kip1) mediate two separate pathways to collaboratively suppress pituitary tumorigenesis. Genes Dev, 12(18), 2899-911 (1998) (Pubitemid 28440148)
122. W. M. Chien, S. Rabin, E. Macias, P. L. Miliani de Marval, K. Garrison, J. Orthel, M. Rodriguez-Puebla and M. L. Fero: Genetic mosaics reveal both cell-autonomous and cell-nonautonomous function of murine p27Kip1. Proc Natl Acad Sci U S A, 103(11), 4122-7 (2006)
123. H. Nagahama, S. Hatakeyama, K. Nakayama, M. Nagata and K. Tomita: Spatial and temporal expression patterns of the cyclin-dependent kinase (CDK) inhibitors p27Kip1 and p57Kip2 during mouse development. Anat Embryol (Berl), 203(2), 77-87 (2001) (Pubitemid 32200295)
124. A. Baldi, V. Ambrogi, D. Mineo, P. Mellone, M. Campioni, G. Citro and T. C. Mineo: Analysis of cell cycle regulator proteins in encapsulated thymomas. Clin Cancer Res, 11(14), 5078-83 (2005) (Pubitemid 41003690)
125. T. C. Mineo, V. Ambrogi, A. Baldi, E. Pompeo and D. Mineo: Recurrent intrathoracic thymomas: potential prognostic importance of cell-cycle protein expression. J Thorac Cardiovasc Surg, 138(1), 40-5 (2009)
126. J. E. McElhaney and R. B. Effros: Immunosenescence: what does it mean to health outcomes in older adults? Curr Opin Immunol, 21(4), 418-24 (2009)
127. F. R. Appelbaum: Who should be transplanted for AML? Leukemia, 15(4), 680-2 (2001) (Pubitemid 32266746)
128. A. M. Holland and M. R. van den Brink: Rejuvenation of the aging T cell compartment. Curr Opin Immunol, 21(4), 454-9 (2009)
129. M. L. Markert, A. Boeck, L. P. Hale, A. L. Kloster, T. M. McLaughlin, M. N. Batchvarova, D. C. Douek, R. A. Koup, D. D. Kostyo, F. E. Ward, H. E. Rice and S. M. Mahaffey: Transplantation of thymus tissue in complete DiGeorge Syndrome. N Engl J Med, 341, 1180-1189 (1999) (Pubitemid 29480656)
130. M. L. Markert, B. H. Devlin, M. J. Alexieff, J. Li, E. A. McCarthy, S. E. Gupton, I. K. Chinn, L. P. Hale, T. B. Kepler, M. He, M. Sarzotti, M. A. Skinner, H. E. Rice and J. C. Hoehner: Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood, 109(10), 4539-47 (2007) (Pubitemid 46743425)
131. M. L. Markert, B. H. Devlin, I. K. Chinn and E. A. McCarthy: Thymus transplantation in complete DiGeorge anomaly. Immunol Res, 44(1-3), 61-70 (2009)
132. B. F. Haynes, M. L. Markert, G. D. Sempowski, D. D. Patel and L. P. Hale: The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection. Annu Rev Immunol, 18, 529-60 (2000) (Pubitemid 30365390)
133. M. L. Markert, M. Sarzotti, D. A. Ozaki, G. D. Sempowski, M. E. Rhein, L. P. Hale, F. Le Deist, M. J. Alexieff, J. Li, E. R. Hauser, B. F. Haynes, H. E. Rice, M. A. Skinner, S. M. Mahaffey, J. Jaggers, L. D. Stein and M. R. Mill: Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients. Blood, 102(3), 1121-30 (2003) (Pubitemid 36917815)
134. M. L. Markert, M. J. Alexieff, J. Li, M. Sarzotti, D. A. Ozaki, B. H. Devlin, D. A. Sedlak, G. D. Sempowski, L. P. Hale, H. E. Rice, S. M. Mahaffey and M. A. Skinner: Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome. Blood, 104(8), 2574-81 (2004) (Pubitemid 39331863)
135. H. E. Rice, M. A. Skinner, S. M. Mahaffey, K. T. Oldham, R. J. Ing, L. P. Hale and M. L. Markert: Thymic transplantation for complete DiGeorge syndrome: medical and surgical considerations. J Pediatr Surg, 39(11), 1607-15 (2004) (Pubitemid 39487986)
136. I. K. Chinn, B. H. Devlin, Y. J. Li and M. L. Markert: Long-term tolerance to allogeneic thymus transplants in complete DiGeorge anomaly. Clin Immunol, 126(3), 277-81 (2008)
137. M. L. Markert, B. H. Devlin, I. K. Chinn, E. A. McCarthy and Y. J. Li: Factors affecting success of thymus transplantation for complete DiGeorge anomaly. Am J Transplant, 8(8), 1729-36 (2008)
138. M. L. Markert, J. G. Marques, B. Neven, B. H. Devlin, E. A. McCarthy, I. K. Chinn, A. S. Albuquerque, S. L. Silva, C. Pignata, G. de Saint Basile, R. M. Victorino, C. Picard, M. Debre, N. Mahlaoui, A. Fischer and A. E. Sousa: First use of thymus transplantation therapy for FOXN1 deficiency (nude/SCID): a report of two cases. Blood, in press (2010)
139. L. Haynes and S. L. Swain: Why aging T cells fail: implications for vaccination. Immunity, 24(6), 663-6 (2006) (Pubitemid 43867372)
140. D. D. Taub and D. L. Longo: Insights into thymic aging and regeneration. Immunol Rev, 205, 72-93 (2005) (Pubitemid 40780178)
141. M. R. van den Brink, O. Alpdogan and R. L. Boyd: Strategies to enhance T-cell reconstitution in immunocompromised patients. Nat Rev Immunol, 4(11), 856-67 (2004) (Pubitemid 39490761)
142. E. J. Wils and J. J. Cornelissen: Thymopoiesis following allogeneic stem cell transplantation: new possibilities for improvement. Blood Rev, 19(2), 89-98 (2005) (Pubitemid 39643114)