Thymus involution and regeneration: Two sides of the same coin?

Nature Reviews Immunology

Volumn 13, Issue 11, 2013, Pages 831-838

  Boehm, Thomas ^a   Swann, Jeremy B ^a  

^a MAX PLANCK INSTITUTE OF IMMUNOBIOLOGY AND EPIGENETICS   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

FORKHEAD BOX PROTEIN N1; PROTEIN; UNCLASSIFIED DRUG;

ADOLESCENCE; CELL COMPARTMENTALIZATION; CELL DIFFERENTIATION; CELLULAR IMMUNITY; EPITHELIUM; EPITHELIUM CELL; INVOLUTION; LYMPHOCYTOPOIESIS; MOLECULAR BIOLOGY; NONHUMAN; ONTOGENY; PHENOTYPE; PHYLOGENY; PHYSIOLOGY; PRIORITY JOURNAL; PROTEIN EXPRESSION; REGENERATION; REVIEW; T LYMPHOCYTE; THYMUS; THYMUS FUNCTION;

ANIMALS; CELL DIFFERENTIATION; CELLULAR MICROENVIRONMENT; EPITHELIAL CELLS; EPITHELIUM; HUMANS; REGENERATION; STEM CELLS; THYMUS GLAND;

EID: 84886782003     PISSN: 14741733     EISSN: 14741741     Source Type: Journal    
DOI: 10.1038/nri3534     Document Type: Review

References (122)

1. Gordon, J. et al. Functional evidence for a single endodermal origin for the thymic epithelium. Nature Immunol. 5, 546-553 (2004). (Pubitemid 38660468)
2. Gordon, J., Bennett, A. R., Blackburn, C. C. & Manley, N. R. Gcm2 and Foxn1 mark early parathyroid-and thymus-specific domains in the developing third pharyngeal pouch. Mech. Dev. 103, 141-143 (2001). (Pubitemid 32457917)
3. Nehls, M., Pfeifer, D., Schorpp, M., Hedrich, H. & Boehm, T. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 372, 103-107 (1994). (Pubitemid 24339492)
4. Bleul, C. C. et al. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 441, 992-996 (2006). (Pubitemid 43980354)
5. Dooley, J., Erickson, M. & Farr, A. G. Lessons from thymic epithelial heterogeneity: FoxN1 and tissue-restricted gene expression by extrathymic, endodermally derived epithelium. J. Immunol. 183, 5042-5049 (2009).
6. Meier, N., Dear, T. N. & Boehm, T. Whn and mHa3 are components of the genetic hierarchy controlling hair follicle differentiation. Mech. Dev. 89, 215-221 (1999). (Pubitemid 29528295)
7. Osada, M. et al. The Wnt signaling antagonist Kremen1 is required for development of thymic architecture. Clin. Dev. Immunol. 13, 299-319 (2006). (Pubitemid 44950046)
8. Rodewald, H.-R. Thymus organogenesis. Annu. Rev. Immunol. 26, 355-388 (2008). (Pubitemid 351600380)
9. Manley, N. R. & Condie, B. G. Transcriptional regulation of thymus organogenesis and thymic epithelial cell differentiation. Prog. Mol. Biol. Transl. Sci. 92, 103-120 (2010).
10. Arnold, J. S. et al. Inactivation of Tbx1 in the pharyngeal endoderm results in 22q11DS malformations. Development 133, 977-987 (2006).
11. Manley, N. R. & Capecchi, M. R. Hox group 3 paralogs regulate the development and migration of the thymus, thyroid, and parathyroid glands. Dev. Biol. 195, 1-15 (1998). (Pubitemid 28146373)
12. Wallin, J. et al. Pax1 is expressed during development of the thymus epithelium and is required for normal T-cell maturation. Development 122, 23-30 (1996). (Pubitemid 26038415)
13. Griffith, A. V. et al. Increased thymus-and decreased parathyroid-fated organ domains in Splotch mutant embryos. Dev. Biol. 327, 216-227 (2009).
14. Hetzer-Egger, C. et al. Thymopoiesis requires Pax9 function in thymic epithelial cells. Eur. J. Immunol. 32, 1175-1181 (2002). (Pubitemid 34428835)
15. Zou, D. et al. Patterning of the third pharyngeal pouch into thymus/parathyroid by Six and Eya1. Dev. Biol. 293, 499-512 (2006).
16. Revest, J. M., Suniara, R. K., Kerr, K., Owen, J. J. T. & Dickson, C. Development of the thymus requires signaling through the fibroblast growth factor receptor R2-IIIb. J. Immunol. 167, 1954-1961 (2001). (Pubitemid 32747500)
17. Jenkinson, W. E., Jenkinson, E. J. & Anderson, G. Differential requirement for mesenchyme in the proliferation and maturation of thymic epithelial progenitors. J. Exp. Med. 198, 325-332 (2003). (Pubitemid 36987857)
18. Jenkinson, W. E., Rossi, S. W., Parnell, S. M., Jenkinson, E. J. & Anderson, G. PDGFRα-expressing mesenchyme regulates thymus growth and the availability of intrathymic niches. Blood 109, 954-960 (2007). (Pubitemid 46220639)
19. Erickson, M. et al. Regulation of thymic epithelium by keratinocyte growth factor. Blood 100, 3269-3278 (2002). (Pubitemid 35217077)
20. Bleul, C. C. & Boehm, T. BMP signaling is required for normal thymus development. J. Immunol. 175, 5213-5221 (2005). (Pubitemid 41456406)
21. Patel, S. R., Gordon, J., Mahbub, F., Blackburn, C. C. & Manley, N. R. Bmp4 and Noggin expression during early thymus and parathyroid organogenesis. Gene Expr. Patterns 6, 794-799 (2006). (Pubitemid 44334730)
22. Gordon, J., Patel, S. R., Mishina, Y. & Manley, N. R. Evidence for an early role for BMP4 signaling in thymus and parathyroid morphogenesis. Dev. Biol. 339, 141-154 (2010).
23. García-Ceca, J. et al. On the role of Eph signalling in thymus histogenesis; EphB2/B3 and the organizing of the thymic epithelial network. Int. J. Dev. Biol. 53, 971-982 (2009).
24. García-Ceca, J. et al. Cell-autonomous role of EphB2 and EphB3 receptors in the thymic epithelial cell organization. Eur. J. Immunol. 39, 2916-2924 (2009).
25. Balciunaite, G. et al. Wnt glycoproteins regulate the expression of FoxN1, the gene defective in nude mice. Nature Immunol. 3, 1102-1108 (2002). (Pubitemid 35363665)
26. Pongracz, J., Hare, K., Harman, B., Anderson, G. & Jenkinson, E. J. Thymic epithelial cells provide Wnt signals to developing thymocytes. Eur. J. Immunol. 33, 1949-1956 (2003). (Pubitemid 37120867)
27. Zuklys, S. et al. Stabilized β-catenin in thymic epithelial cells blocks thymus development and function. J. Immunol. 182, 2997-3007 (2009).
28. Osada, M. et al. DKK1 mediated inhibition of Wnt signaling in postnatal mice leads to loss of TEC progenitors and thymic degeneration. PLoS ONE 5, e9062 (2010).
29. Kvell, K. et al. Wnt4 and LAP2α as pacemakers of thymic epithelial senescence. PloS ONE 5, e10701 (2010).
30. Heinonen, K. M. et al. Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors. Blood 118, 5163-5173 (2011).
31. Varecza, Z. et al. Multiple suppression pathways of canonical Wnt signalling control thymic epithelial senescence. Mech. Ageing Dev. 132, 249-256 (2011).
32. Cheng, L. et al. Postnatal tissue-specific disruption of transcription factor FoxN1 triggers acute thymic atrophy. J. Biol. Chem. 285, 5836-5847 (2010).
33. Corbeaux, T. et al. Thymopoiesis in mice depends on a Foxn1-positive thymic epithelial cell lineage. Proc. Natl Acad. Sci. USA 107, 16613-16618 (2010).
34. Chen, L., Xiao, S. & Manley, N. R. Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner. Blood 113, 567-574 (2009).
35. Guo, J. et al. Morphogenesis and maintenance of the 3D thymic medulla and prevention of nude skin phenotype require FoxN1 in pre-and post-natal K14 epithelium. J. Mol. Med. 89, 263-277 (2011).
36. Guo, J. et al. Deletion of FoxN1 in the thymic medullary epithelium reduces peripheral T cell responses to infection and mimics changes of aging. PLoS ONE 7, e34681 (2012).
37. Vroegindeweij, E. et al. Thymic cysts originate from Foxn1 positive thymic medullary epithelium. Mol. Immunol. 47, 1106-1113 (2010).
38. Dooley, J., Erickson, M., Roelink, H. & Farr, A. G. Nude thymic rudiment lacking functional foxn1 resembles respiratory epithelium. Dev. Dyn. 233, 1605-1612 (2005). (Pubitemid 40995158)
39. Nehls, M. et al. Two genetically separable steps in the differentiation of thymic epithelium. Science 272, 886-889 (1996). (Pubitemid 26154594)
40. Blackburn, C. C. et al. The nu gene acts cell-autonomously and is required for differentiation of thymic epithelial progenitors. Proc. Natl Acad. Sci. USA 93, 5742-5746 (1996). (Pubitemid 26190750)
41. Rossi, S. W., Jenkinson, W. E., Anderson, G. & Jenkinson, E. J. Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 441, 988-991 (2006). (Pubitemid 43980353)
42. Rossi, S. W. et al. Redefining epithelial progenitor potential in the developing thymus. Eur. J. Immunol. 37, 2411-2418 (2007). (Pubitemid 47423612)
43. Rodewald, H.-R., Paul, S., Haller, C., Bluethmann, H. & Blum, C. Thymus medulla consisting of epithelial islets each derived from a single progenitor. Nature 414, 763-768 (2001). (Pubitemid 34000775)
44. + progenitors. Eur. J. Immunol. 43, 589-594 (2013).
45. Ohigashi, I. et al. Aire-expressing thymic medullary epithelial cells originate from p5t-expressing progenitor cells. Proc. Natl Acad. Sci. USA 110, 9885-9890 (2013).
46. Akiyama, T. et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29, 423-437 (2008).
47. Hikosaka, Y. et al. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 29, 438-450 (2008).
48. + thymocytes control mature medullary thymic epithelial cell cellularity. Immunity 29, 451-463 (2008).
49. White, A. J. et al. Lymphotoxin signals from positively selected thymocytes regulate the terminal differentiation of medullary thymic epithelial cells. J. Immunol. 185, 4769-4776 (2010).
50. + medullary epithelium. Immunity 36, 427-437 (2012).
51. Li, M. et al. Skin abnormalities generated by temporally controlled RXRa mutations in mouse epidermis. Nature 407, 633-636 (2000).
52. Hamazaki, Y. et al. Medullary thymic epithelial cells expressing Aire represent a unique lineage derived from cells expressing claudin. Nature Immunol. 8, 304-311 (2007). (Pubitemid 46745380)
53. Rossi, S. W. et al. Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood 109, 3803-3811 (2007). (Pubitemid 46641731)
54. Gordon, J. et al. Specific expression of lacZ and cre recombinase in fetal thymic epithelial cells by multiplex gene targeting at the Foxn1 locus. BMC Dev. Biol. 7, 69 (2007).
55. Soza-Ried, C, Bleul, C. C, Schorpp, M. & Boehm, T Maintenance of thymic epithelial phenotype requires extrinsic signals in mouse and zebrafish. J. Immunol. 181, 5272-5277 (2008).
56. Park, C. S. et al. Differential lineage specification of thymic epithelial cells from bipotent precursors revealed by TSCOT promoter activities. Genes Immun. 14, 401-406 (2013).
57. Hong, R. The DiGeorge anomaly. Clin. Rev. Allergy Immunol. 20, 43-60 (2001). (Pubitemid 32221664)
58. van Gent, R. et al. Long-term restoration of the human T-cell compartment after thymectomy during infancy: a role for thymic regeneration? Blood 118, 627-634 (2011).
59. Sauce, D. et al. Lymphopenia-driven homeostatic regulation of naive T cells in elderly and thymectomized young adults. J. Immunol. 189, 5541-5548 (2012).
60. Eysteinsdottir, J. H. et al. The influence of partial or total thymectomy during open heart surgery in infants on the immune function later in life. Clin. Exp. Immunol. 136, 349-355 (2004). (Pubitemid 38543456)
61. Inami, Y. et al. Differentiation of induced pluripotent stem cells to thymic epithelial cells by phenotype. Immunol. Cell Biol. 89, 314-321 (2011).
62. Hidaka, K. et al. Differentiation of pharyngeal endoderm from mouse embryonic stem cell. Stem Cells Dev. 19, 1735-1743 (2010).
63. Lai, L. et al. Mouse embryonic stem cell-derived thymic epithelial cell progenitors enhance T-cell reconstitution after allogeneic bone marrow transplantation. Blood 118, 3410-3418 (2011).
64. Lai, L. & Jin, J. Generation of thymic epithelial cell progenitors by mouse embryonic stem cells. Stem Cells 27, 3012-3020 (2009).
65. Green, M. D. et al. Generation of anterior foregut endoderm from human embryonic and induced pluripotent stem cells. Nature Biotech. 29, 267-272 (2011).
66. Müller, S. M. et al. Gene targeting of VEGF-A in thymus epithelium disrupts thymus blood vessel architecture. Proc. Natl Acad. Sci. USA 102, 10587-10592 (2005). (Pubitemid 41061598)
67. Isotani, A., Hatayama, H., Kaseda, K., Ikawa, M. & Okabe, M. Formation of a thymus from rat ES cells in xenogeneic nude mouse-rat ES chimeras. Genes Cells 16, 397-405 (2011).
68. Bonfanti, P. et al. Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells. Nature 466, 978-982 (2010).
69. Parent, A. V. et al. Generation of functional thymic epithelium from human embryonic stem cells that supports host T cell development. Cell Stem Cell 13, 219-229 (2013).
70. Sun, X. et al. Directed differentiation of human embryonic stem cells into thymic epithelial progenitorlike cells reconstitutes the thymic microenvironment in vivo. Cell Stem Cell 13, 230-236 (2013).
71. Pinto, S. et al. An organotypic coculture model supporting proliferation and differentiation of medullary thymic epithelial cells and promiscuous gene expression. J. Immunol. 190, 1085-1093 (2013).
72. Dervovic, D. & Zúñiga-Pflücker, J. C. Positive selection of T cells, an in vitro view. Semin. Immunol. 22, 276-286 (2010).
73. Beaudette-Zlatanova, B. C. et al. A human thymic epithelial cell culture system for the promotion of lymphopoiesis from hematopoietic stem cells. Exp. Hematol. 39, 570-579 (2011).
74. Calderón, L. & Boehm, T. Synergistic, context-dependent and hierarchical functions of epithelial components in thymic microenvironments. Cell 149, 159-172 (2012).
75. Hozumi, K. et al. Delta-like 4 is indispensable in thymic environment specific for T cell development. J. Exp. Med. 205, 2507-2513 (2008).
76. Koch, U. et al. Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. J. Exp. Med. 205, 2515-2523 (2008).
77. Mori, K., Itoi, M., Tsukamoto, N., Kubo, H. & Amagai, T. The perivascular space as a path of hematopoietic progenitor cells and mature T cells between the blood circulation and the thymic parenchyma. Int. Immunol. 19, 745-753 (2007). (Pubitemid 47073264)
78. Zachariah, M. A. & Cyster, J. G. Neural crest-derived pericytes promote egress of mature thymocytes at the corticomedullary junction. Science 328, 1129-1135 (2010).
79. Takahama, Y. Journey through the thymus: stromal guides for T-cell development and selection. Nature Rev. Immunol. 6, 127-135 (2006). (Pubitemid 43361588)
80. Petrie, H. T. & Zúñiga-Pflücker, J. C. Zoned out: functional mapping of stromal signaling microenvironments in the thymus. Annu. Rev. Immunol. 25, 649-679 (2007). (Pubitemid 46697920)
81. Benz, C., Heinzel, K. & Bleul, C. C. Homing of immature thymocytes to the subcapsular microenvironment within the thymus is not an absolute requirement for T cell development. Eur. J. Immunol. 34, 3652-3663 (2004). (Pubitemid 40012183)
82. Roberts, N. A. et al. Absence of thymus crosstalk in the fetus does not preclude hematopoietic induction of a functional thymus in the adult. Eur. J. Immunol. 39, 2395-2402 (2009).
83. Hoot, G. P. & Kettman, J. R. Extra-thymic immature T cells: development in polyoma virus-induced murine salivary gland tumors. Eur. J. Immunol. 19, 1991-1998 (1989). (Pubitemid 20017702)
84. Kendall, M. D. & Ward, P. Erythropoiesis in an avian thymus. Nature 249, 366-367 (1974).
85. Boehm, T. Design principles of adaptive immune systems. Nature Rev. Immunol. 11, 307-317 (2011).
86. Bajoghli, B. et al. A thymus candidate in lampreys. Nature 470, 90-94 (2011).
87. Boehm, T., Hess, I. & Swann, J. B. Evolution of lymphoid tissues. Trends Immunol. 33, 315-321 (2012).
88. Boehm, T. et al. VLR-based adaptive immunity. Annu. Rev. Immunol. 30, 203-220 (2012).
89. Boehm, T., Iwanami, N. & Hess, I. Evolution of the immune system in the lower vertebrates. Ann. Rev. Genom. Hum. Genet. 13, 127-149 (2012).
90. Hess, I. & Boehm, T. Intravital imaging of thymopoiesis reveals dynamic lympho-epithelial interactions. Immunity 36, 298-309 (2012).
91. Haynes, B. F. & Heinly, C. S. Early human T cell development: analysis of the human thymus at the time of initial entry of hematopoietic stem cells into the fetal thymic microenvironment. J. Exp. Med. 181, 1445-1458 (1995).
92. Gray, D. H. D. et al. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 108, 3777-3785 (2006). (Pubitemid 44864559)
93. Simpson, L. O. Studies on the NZB mouse thymus. I. Thymus weight relationships to age and body weight from birth to old age. Am. J. Anat. 141, 127-132 (1974).
94. Dudakov, J. A. et al. Sex steroid ablation enhances hematopoietic recovery following cytotoxic antineoplastic therapy in aged mice. J. Immunol. 183, 7084-7094 (2009).
95. Griffith, A. V., Fallahi, M., Venables, T. & Petrie, H. T. Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth. Aging Cell 11, 169-177 (2012).
96. Lynch, H. E. et al. Thymic involution and immune reconstitution. Trends Immunol. 30, 366-373 (2009).
97. + T-cell pool with aging governed by T-cell receptor:pMHC interactions. Proc. Natl Acad. Sci. USA 108, 13694-13699 (2011)
98. Martins, V. C. et al. Thymus-autonomous T cell development in the absence of progenitor import. J. Exp. Med. 209, 1409-1417 (2012).
99. Boehm, T. Self-renewal of thymocytes in the absence of competitive precursor replenishment. J. Exp. Med. 209, 1397-1400 (2012).
100. Min, H., Montecino-Rodriguez, E. & Dorshkind, K. Reassessing the role of growth hormone and sex steroids in thymic involution. Clin. Immunol. 118, 117-123 (2006). (Pubitemid 43012054)
101. + cells generate fewer T cells in vitro with increasing age and following chemotherapy. Br. J. Haematol. 104, 801-808 (1999). (Pubitemid 29143501)
102. Itoi, M., Tsukamoto, N. & Amagai, T. Expression of Dll4 and CCL25 in Foxn1-negative epithelial cells in the post-natal thymus. Int. Immunol. 19, 127-132 (2007). (Pubitemid 46179007)
103. Castermans, E. et al. Thymic recovery after allogeneic hematopoietic cell transplantation with non-myeloablative conditioning is limited to patients younger than 60 years of age. Haematologica 96, 298-306 (2011).
104. Toubert, A., Glauzy, S., Douay, C. & Clave, E. Thymus and immune reconstitution after allogeneic hematopoietic stem cell transplantation in humans: never say never again. Tissue Antigens 79, 83-89 (2012).
105. Zook, E. C. et al. Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells. Blood 118, 5723-5731 (2011).
106. Garfin, P. M. et al. Inactivation of the RB family prevents thymus involution and promotes thymic function by direct control of Foxn1 expression. J. Exp. Med. 210, 1087-1097 (2013).
107. Dooley, J., Erickson, M., Larochelle, W. J., Gillard, G. O. & Farr, A. G. FGFR2IIIb signaling regulates thymic epithelial differentiation. Dev. Dyn. 236, 3459-3471 (2007). (Pubitemid 350276402)
108. Seggewiss, R. et al. Keratinocyte growth factor augments immune reconstitution after autologous hematopoietic progenitor cell transplantation in rhesus macaques. Blood 110, 441-449 (2007). (Pubitemid 47026867)
109. Chu, Y. W. et al. Exogenous insulin-like growth factor 1 enhances thymopoiesis predominantly through thymic epithelial cell expansion. Blood 112, 2836-2846 (2008).
110. Talaber, G. et al. Wnt-4 protects thymic epithelial cells against dexamethasone-induced senescence. Rejuven. Res. 14, 241-248 (2011).
111. Hauri-Hohl, M. M. et al. TGF-β signaling in thymic epithelial cells regulates thymic involution and postirradiation reconstitution. Blood 112, 626-634 (2008).
112. Nunes-Alves, C., Nobrega, C., Behar, S. M. & Correia-Neves, M. Tolerance has its limits: how the thymus copes with infection. Trends Immunol. http://dx.doi.org/10.1016/j.it.2013.06.004 (2013).
113. Papadopoulou, A. S. et al. The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-α receptor. Nature Immunol. 13, 181-187 (2012).
114. Youm, Y.-H. et al. The NLRP3 inflammasome promotes age-related thymic demise and immunosenescence. Cell Rep. 1, 56-68 (2012).
115. Dudakov, J. A. et al. Interleukin-22 drives endogenous thymic regeneration in mice. Science 336, 91-95 (2012).
116. Jenkinson, W. E., Bacon, A., White, A. J., Anderson, G. & Jenkinson, E. J. An epithelial progenitor pool regulates thymus growth. J. Immunol. 181, 6101-6108 (2008).
117. Rode, I. & Boehm, T. Regenerative capacity of adult cortical thymic epithelial cells. Proc. Natl Acad. Sci. USA 109, 3463-3468 (2012).
118. Doupé, D. P. et al. A single progenitor population switches behavior to maintain and repair esophageal epithelium. Science 337, 1091-1093 (2012).
119. Mascré, G. et al. Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature 489, 257-262 (2012).
120. Markert, M. L., Devlin, B. H., Chinn, I. K. & McCarthy, E. A. Thymus transplantation in complete DiGeorge anomaly. Immunol. Res. 44, 61-70 (2009).
121. Ciupe, S. M., Devlin, B. H., Markert, M. L. & Kepler, T. B. The dynamics of T-cell receptor repertoire diversity following thymus transplantation for DiGeorge anomaly. PloS Comput. Biol. 5, e1000396 (2009).
122. + T-cell expansions that are distinctly modulated upon thymic transplantation. PLoS ONE 7, e37042 (2012).