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  • Review Article
  • Published:

Developing a new paradigm for thymus organogenesis

Nature Reviews Immunology volume 4, pages 278–289 (2004)Cite this article

Key Points

  • The mature thymus contains two anatomically and functionally distinct stromal compartments, the cortex and medulla. Each compartment contains several phenotypically distinct thymic epithelial-cell (TEC) types. Proper development and organization of these different TECs is essential for thymocyte development and repertoire selection.

  • The embryonic origin of the cortical and medullary TEC compartments is controversial. Two models exist: the 'dual-origin' model, in which cortical TECs derive from the pharyngeal ectoderm, whereas medullary TECs derive from the pharyngeal endoderm; and the 'single-origin' model, in which all TECs are of endodermal origin. The dual-origin model has been widely accepted and is the 'textbook' model.

  • A recent study has tested the dual- and single-origin models directly in mice, through analysis of the fate of the pharyngeal ectoderm and the potency of the pharyngeal endoderm. These data support a single, endodermal origin for both cortical and medullary TECs, and provide direct evidence against the dual-origin model.

  • Recent evidence has also suggested the existence of a common thymic epithelial progenitor cell for both cortical and medullary TECs, and has indicated a clonal origin for individual medullary islets. These studies are consistent with a single-origin model.

  • Analysis of the genes that control early thymus organogenesis has identified a Hox–Pax–Eya–Six transcription factor network that is required for initial thymus organogenesis. These factors are co-expressed only in the endoderm, again supporting a single origin for all TECs. The gene(s) responsible for establishing thymus identity, however, has not yet been identified.

  • Various signalling pathways, including fibroblast growth factors (Fgfs), Wnts and bone morphogenetic proteins (Bmps), have also been implicated in mediating epithelial–mesenchymal interactions during organogenesis, TEC differentiation and TEC–thymocyte interactions. However, the initiation signal for thymus organogenesis remains elusive.

  • Recent studies have challenged the concept that establishment of the cortical and medullary compartments is regulated by 'cross-talk' with lymphocytes, providing evidence that TEC differentiation can be divided into initial lymphocyte-independent and later lymphocyte-dependent stages, and that forkhead box N1 (Foxn1) is required for both of these stages.

  • Together, these advances have created a new framework, within which future analysis of thymus organogenesis, TEC differentiation and TEC–thymocyte interactions can be addressed.

Abstract

The mature thymic epithelium is complex, with two major compartments — the cortex and the medulla — each containing several functionally distinct epithelial-cell types. There is considerable debate as to the embryonic origins of these different thymic epithelial-cell subpopulations. The textbook view is a dual origin, with cortical thymic epithelium arising from the ectoderm and medullary thymic epithelium originating in the endoderm. However, the literature has been divided on this issue since it was first considered. In this review, we discuss recent embryological, functional, genetic and molecular data that collectively support a new model of thymus organogenesis and patterning.

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Figure 1: Thymus structure and function.
Figure 2: Design of transplantation experiments showing that endodermal cells can generate a functional thymus.
Figure 3: Evidence for a common progenitor/stem cell for thymic epithelial cells (TECs).
Figure 4: Two possible models of thymic epithelial-cell (TEC) development.
Figure 5: A new model of thymus organogenesis.

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References

  1. Miller, J. F. A. P. Immunological function of the thymus. Lancet 2, 748–749 (1961).

    Article  CAS  PubMed  Google Scholar 

  2. Anderson, G. & Jenkinson, E. Lymphostromal interactions in thymus development and function. Nature. Rev. Immunol. 1, 31–40 (2001).

    Article  CAS  Google Scholar 

  3. Boyd, R. L. et al. The thymic microenvironment. Immunol. Today 14, 445–459 (1993).

    Article  CAS  PubMed  Google Scholar 

  4. Von Gaudecker, B., Kendall, M. D. & Ritter, M. A. Immuno-electron microscopy of the thymic epithelial microenvironment. Microsc. Res. Tech. 38, 237–249 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Ritter, M. A. & Boyd, R. L. Development in the thymus: it takes two to tango. Immunol. Today 14, 462–469 (1993).

    Article  CAS  PubMed  Google Scholar 

  6. van Ewijk, W., Hollander, G., Terhorst, C. & Wang, B. Stepwise development of thymic microenvironments in vivo is regulated by thymocyte subsets. Development 127, 1583–1591 (2000).

    CAS  PubMed  Google Scholar 

  7. Prockop, S. & Petrie, H. T. Cell migration and the anatomic control of thymocyte precursor differentiation. Semin. Immunol. 12, 435–444 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Lind, E. F., Prockop, S. E., Porritt, H. E. & Petrie, H. T. Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development. J. Exp. Med. 194, 127–134 (2001). This study used immunofluorescence with multiple thymocyte- and stromal-specific markers to localize different thymocyte subsets in the adult thymus. The data provide strong support for a model in which thymocyte migration and differentiation are both dependent on signals from specific regions in the thymus.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Plotkin, J., Prockop, S. E., Lepique, A. & Petrie, H. T. Critical role for CXCR4 signaling in progenitor localization and T cell differentiation in the postnatal thymus. J. Immunol. 171, 4521–4527 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Anderson, G., Owen, J. J. T., Moore, N. C. & Jenkinson, E. J. Thymic epithelial cells provide unique signals for positive selection of CD4+CD8+ thymocytes in vitro. J. Exp. Med. 179, 2027–2031 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Ge, Q. & Chen, W. -F. Effect of murine thymic epithelial cell line (MTEC1) on the functional expression of CD4+CD8− thymocytes subgroups. Int. Immunol. 12, 1127–1133 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Kyewski, B., Derbinski, J., Gotter, J. & Klein, L. Promiscuous gene expression and central T-cell tolerance: more than meets the eye. Trends Immunol. 23, 364–371 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Derbinski, J., Schulte, A., Kyewski, B. & Klein, L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nature Immunol. 2, 1032–1039 (2001).

    Article  CAS  Google Scholar 

  14. Farr, A. G., Dooley, J. L. & Erickson, M. Organization of thymic medullary epithelial heterogeneity: implications for mechanisms of epithelial differentiation. Immunol. Rev. 189, 20–27 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Farr, A. G. & Rudensky, A. Medullary thymic epithelium: a mosaic of epithelial 'self'? J. Exp. Med. 188, 1–4 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Anderson, M. S. et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 298, 1395–1401 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Anderson, G., Harman, B. C., Hare, K. J. & Jenkinson, E. J. Microenvironmental regulation of T cell development in the thymus. Semin. Immunol. 12, 457–464 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Petrie, H. T. Cell migration and the control of post-natal T-cell lymphopoiesis in the thymus. Nature Rev. Immunol. 3, 859–866 (2003).

    Article  CAS  Google Scholar 

  19. Schmitt, T. M. & Zuniga-Pflucker, J. C. Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity 17, 749–756 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Hare, K. J., Jenkinson, E. J. & Anderson, G. In vitro models of T cell development. Semin. Immunol. 11, 3–12 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Poznansky, M. C. et al. Efficient generation of human T cells from a tissue-engineered thymic organoid. Nature Biotech. 18, 729–734 (2000).

    Article  CAS  Google Scholar 

  22. Manley, N. R. Thymus organogenesis and molecular mechanisms of thymic epithelial cell differentiation. Semin. Immunol. 12, 421–428 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Manley, N. R. & Blackburn, C. C. A developmental look at thymus organogenesis: where do the non-hematopoetic cells in the thymus come from? Curr. Opin. Immunol. 15, 225–232 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Cordier, A. C. & Haumont, S. M. Development of thymus, parathyroids and ultimo-branchial bodies in NMRI and nude mice. Am. J. Anat. 157, 227–263 (1980).

    Article  CAS  PubMed  Google Scholar 

  25. 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).

    Article  CAS  PubMed  Google Scholar 

  26. Le Lievre, C. S. & Le Douarin, N. M. Mesenchymal derivatives of the neural crest: analysis of chimaeric quail and chick embryos. J. Embryol. Exp. Morph. 34, 125–154 (1975).

    CAS  PubMed  Google Scholar 

  27. Jiang, X., Rowitch, D. H., Soriano, P., McMahon, A. P. & Sucov, H. M. Fate of the mammalian cardiac neural crest. Development 127, 1607–1616 (2000).

    CAS  PubMed  Google Scholar 

  28. Auerbach, R. Morphogenetic interactions in the development of the mouse thymus gland. Dev. Biol. 2, 271–284 (1960).

    Article  CAS  PubMed  Google Scholar 

  29. Manley, N. R. & Capecchi, M. R. The role of Hoxa-3 in mouse thymus and thyroid development. Development 121, 1989–2003 (1995).

    CAS  PubMed  Google Scholar 

  30. Ohnemus, S. et al. Aortic arch and pharyngeal phenotype in the absence of BMP-dependent neural crest in the mouse. Mech. Dev. 119, 127–135 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Petrie, H. T. Role of thymic organ structure and stromal composition in steady-state postnatal T-cell production. Immunol. Rev. 189, 8–20 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Cordier, A. C. & Heremans, J. F. Nude mouse embryo: ectodermal nature of the primordial thymic defect. Scand. J. Immunol. 4, 193–196 (1975).

    Article  CAS  PubMed  Google Scholar 

  33. Janeway, C. A., Travers, P., Walport, M. & Shlomchik, M. J. Immunobiology: The immune system in health and disease. (Garland Publishing, New York, 2001).

    Google Scholar 

  34. Parham, P. The Immune System (Garland Publishing, New York, 2000).

    Google Scholar 

  35. Blackburn, C. C. et al. One for all and all for one: thymic epithelial stem cells and regeneration. Trends Immunol. 23, 391–395 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. van Vliet, E., Jenkinson, E. J., Kingston, R., Owen, J. J. T. & van Ewijk, W. Stromal cell types in the developing thymus of the normal and nude mouse embryo. Eur. J. Immunol. 15, 675–681 (1985).

    Article  CAS  PubMed  Google Scholar 

  37. Owen, J. J. & Jenkinson, E. J. Early events in T lymphocyte genesis in the fetal thymus. Am. J. Anat. 170, 301–310 (1984).

    Article  CAS  PubMed  Google Scholar 

  38. Kingston, R., Jenkinson, E. J. & Owen, J. J. Characterization of stromal cell populations in thedeveloping thymus of normal and nude mice. Eur. J. Immunol. 14, 1052–1056 (1984).

    Article  CAS  PubMed  Google Scholar 

  39. Le Douarin, N. M. & Jotereau, F. V. Tracing of cells of the avian thymus through embryonic life in interspecific chimeras. J. Exp. Med. 142, 17–40 (1975). This study used chick–quail chimaeras to prove the extrathymic origin of T cells. In addition, this study showed that transplanted pharyngeal endoderm is sufficient to generate a complete thymus in an ectopic location, even before formation of the pharyngeal pouch.

    Article  CAS  PubMed  Google Scholar 

  40. Gordon, J. et al. Functional evidence for a single endodermal origin for the thymic epithelium. Nature Immunol. (in the press).

  41. Moore-Scott, B. A., Gordon, J., Blackburn, C. C., Condie, B. G. & Manley, N. R. A new serum-free in vitro culture technique for mid gestation mouse embryos. Genesis 35, 164–168 (2003).

    Article  PubMed  Google Scholar 

  42. Bogden, A. E. et al. Growth of human tumor xenografts implanted under the renal capsule of normal immunocompetent mice. Exp. Cell Biol. 47, 281–293 (1979).

    CAS  PubMed  Google Scholar 

  43. Zinkernagel, R. M. et al. Restriction specificities, alloreactivity, and allotolerance expressed by T cells from nude mice reconstituted with H–2-compatible or-incompatible thymus grafts. J. Exp. Med. 151, 376–399 (1980).

    Article  CAS  PubMed  Google Scholar 

  44. Bennett, A. R. et al. Identification and characterization of thymic epithelial progenitor cells. Immunity 16, 803–814 (2002). Together with reference 52, this important study provides the first functional evidence that a common epithelial progenitor cell might give rise to all thymic epithelial-cell (TEC) subtypes. These papers show that a discrete population of embryonic TECs, identified using monoclonal antibodies MTS20 (Ref. 44) and/or MTS24 (Refs 44,52), are sufficient to establish an organized, fully functional thymus in an ectopic grafting assay.

    Article  CAS  PubMed  Google Scholar 

  45. 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). This study showed that the nude defect is cell-autonomous through analysis of thymic lobes in chimeric mice generated by aggregation of nude and wild-type embryos. The marker analysis in this work also defined the phenotype of nude presumptive TECs that was later used in references 44 and 52 to identify embryonic thymic epithelial progenitor cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Klug, D. B. et al. Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc. Natl Acad. Sci. USA 95, 11822–11827 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Godfrey, D. I., Izon, D. J., Tucek, C. L., Wilson, T. J. & Boyd, R. L. The phenotypic heterogeneity of mouse thymic stromal cells. Immunology 70, 66–74 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang, B. et al. A block in both early T lymphocyte and natural killer cell development in transgenic mice with high-copy numbers of the human CD3E gene. Proc. Natl Acad. Sci. USA 91, 9402–9406 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hollander, G. A. et al. Developmental control point in the induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature 373, 350–353 (1995).

    Article  CAS  PubMed  Google Scholar 

  50. Tokoro, Y. et al. A mouse carrying genetic defect in the choice between T and B lymphocytes. J. Immunol. 161, 4591–4598 (1998).

    CAS  PubMed  Google Scholar 

  51. Klug, D. B., Carter, C., Gimenez-Conti, I. B. & Richie, E. R. Cutting edge: thymocyte-independent and thymocyte-dependent phases of epithelial patterning in the fetal thymus. J. Immunol. 169, 2842–2845 (2002). This study investigated whether the initial stages of TEC differentiation depend on thymocyte-derived signals, by comparing TEC-subset development in wild-type, Ikaros -null and Rag2/common γ-chain-deficient mice. The data indicate that initial TEC differentiation is thymocyte independent, but that thymocyte-derived signals are subsequently required to elaborate/maintain the cortical and medullary compartments.

    Article  CAS  PubMed  Google Scholar 

  52. Gill, J., Malin, M., Hollander, G. A. & Boyd, R. Generation of a complete thymic microenvironment by MTS24+ thymic epithelial cells. Nature Immunol. 3, 635–642 (2002).

    Article  CAS  Google Scholar 

  53. 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). This study investigated the embryonic origins of TECs through analysis of thymus development in chimeric mice. The data show that the thymic medulla arises as a series of independent clonal islets, and reveal a putative 'thymus medulla epithelial stem cell' activity that persists until at least embryonic day 16.5 (E16.5).

    Article  CAS  PubMed  Google Scholar 

  54. Rodewald, H. R. Thymus epithelial cell reaggregate grafts. Curr. Top. Microbiol. Immunol. 251, 101–108 (2000).

    CAS  PubMed  Google Scholar 

  55. Gilbert, S. F. Developmental Biology (Sinauer Associates, Inc., Sunderland, Massachusetts, 2000).

    Google Scholar 

  56. Anderson, M., Anderson, S. K. & Farr, A. G. Thymic vasculature: organizer of the medullary epithelial compartment? Int. Immunol. 12, 1105–1110 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Chisaka, O. & Capecchi, M. R. Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1. 5. Nature 350, 473–479 (1991).

    Article  CAS  PubMed  Google Scholar 

  58. 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).

    CAS  PubMed  Google Scholar 

  59. Peters, H., Neubuser, A., Kratochwil, K. & Balling, R. Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes Dev. 12, 2735–2747 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hetzer-Egger, C. et al. Thymopoiesis requires Pax9 function in thymic epithelial cells. Eur. J. Immunol. 32, 1175–1181 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Xu, P. X. et al. Eya1 is required for the morphogenesis of mammalian thymus, parathyroid and thyroid. Development 129, 3033–3044 (2002).

    CAS  PubMed  Google Scholar 

  62. Pignoni, F. et al. The eye-specification proteins So and Eya form a complex and regulate multiple steps in Drosophila eye development. Cell 91, 881–891 (1997).

    Article  CAS  PubMed  Google Scholar 

  63. Chisaka, O. & Capecchi, M. R. Regionally restricted devlopmental defects resulting from targeted disruption of the mouse homeobox gene hox-1. 5. Nature 350, 473–479 (1991).

    Article  CAS  PubMed  Google Scholar 

  64. Su, D., Ellis, S., Napier, A., Lee, K. & Manley, N. R. Hoxa3 and Pax1 regulate epithelial cell death and proliferation during thymus and parathyroid organogenesis. Dev. Biol. 236, 316–329 (2001). This study used three-dimensional reconstructions and gene-expression studies to show a genetic interaction between Hoxa3 and Pax1 transcription factors, indicating they are in a common pathway for thymus and parathyroid organogenesis. They further showed that this pathway regulates TEC survival, proliferation and differentiation in the fetal thymus.

    Article  CAS  PubMed  Google Scholar 

  65. Laclef, C., Souil, E., Demignon, J. & Maire, P. Thymus, kidney and craniofacial abnormalities in Six 1 deficient mice. Mech. Dev. 120, 669–679 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Krumlauf, R. Hox genes in vertebrate development. Cell 78, 191–201 (1994).

    Article  CAS  PubMed  Google Scholar 

  67. Kim, J. et al. Isolation and characterization of mammalian homologs of the Drosophila gene glial cells missing. Proc. Natl Acad. Sci. USA 95, 12364–12369 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gunther, T. et al. Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. Nature 406, 199–203 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. 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, 103–106 (1994).

    Article  CAS  PubMed  Google Scholar 

  70. Flanagan, S. P. 'Nude', a new hairless gene with pleiotropic effects in the mouse. Genet. Res. 8, 295–309 (1966).

    Article  CAS  PubMed  Google Scholar 

  71. Pantelouris, E. M. Absence of thymus in a mouse mutant. Nature 217, 370–371 (1968).

    Article  CAS  PubMed  Google Scholar 

  72. Nehls, M. et al. Two genetically separable steps in the differentiation of thymic epithelium. Science 272, 886–889 (1996).

    Article  CAS  PubMed  Google Scholar 

  73. Balciunaite, G. et al. Wnt glycoproteins regulate the expression of FoxN1, the gene defective in nude mice. Nature Immunol. 3, 1102–1108 (2002). The authors reported that Wnt signalling can positively regulate Foxn1 gene expression in TEC lines. And also showed that Wnts are expressed in the pharyngeal pouch endoderm and thymus, and therefore might regulate expression of Foxn1 in vivo.

    Article  CAS  Google Scholar 

  74. Jackson, M. et al. Cloning and characterization of Ehox, a novel homeobox gene essential for embryonic stem cell differentiation. J. Biol. Chem. 277, 38683–38692 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Jackson, M. et al. Expression of a novel homeobox gene Ehox in trophoblast stem cells and pharyngeal pouch endoderm. Dev. Dyn. 228, 740–744 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. 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).

    Article  CAS  PubMed  Google Scholar 

  77. Franz, T. Persistent truncus arteriosus in the Splotch mutant mouse. Anat. Embryol. (Berl) 180, 457–464 (1989).

    Article  CAS  Google Scholar 

  78. Conway, S. J., Henderson, D. J. & Copp, A. J. Pax3 is required for cardiac neural crest migration in the mouse: evidence from the splotch (Sp2H) mutant. Development 124, 505–514 (1997).

    CAS  PubMed  Google Scholar 

  79. Epstein, J. A. et al. Migration of cardiac neural crest cells in Splotch embryos. Development 127, 1869–1878 (2000).

    CAS  PubMed  Google Scholar 

  80. Bockman, D. E. & Kirby, M. L. Dependence of thymus development on derivatives of the neural crest. Science 223, 498–500 (1984).

    Article  CAS  PubMed  Google Scholar 

  81. Bockman, D. E. & Kirby, M. L. Neural crest function in thymus development. Immunol. Ser. 45, 451–467 (1989).

    CAS  PubMed  Google Scholar 

  82. Soriano, P. The PDGF-α receptor is required for neural crest cell development and for normal patterning of the somites. Development 124, 2691–2700 (1997).

    CAS  PubMed  Google Scholar 

  83. Frank, D. U. et al. An Fgf8 mouse mutant phenocopies human 22q11 deletion syndrome. Development 129, 4591–4603 (2002).

    CAS  PubMed  Google Scholar 

  84. Revest, J. M., Suniara, R. K., Kerr, K., Owen, J. J. & Dickson, C. Development of the thymus requires signaling through the fibroblast growth factor receptor R2-IIIb. J. Immunol. 167, 1954–1961 (2001). This study, which uses a fibroblast growth factor receptor 2 isoform IIIb ( Fgfr2-IIIb )-knockout mouse to analyse the role of Fgf signalling in early thymus organogenesis, indicates that an Fgf signal from the mesenchyme is required for growth but not initial formation of the thymic primordium. TEC differentiation however is relatively normal in these mice, indicating that signals other than Fgf7 and Fgf10 control at least some aspects of TEC proliferation and differentiation.

    Article  CAS  PubMed  Google Scholar 

  85. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Martin, G. R. The roles of FGFs in the early development of vertebrate limbs. Genes Dev. 12, 1571–1586 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Hogan, B. L. & Yingling, J. M. Epithelial/mesenchymal interactions and branching morphogenesis of the lung. Curr. Opin. Genet. Dev. 8, 481–486 (1998).

    Article  CAS  PubMed  Google Scholar 

  88. Meyers, E. N., Lewandoski, M. & Martin, G. R. An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination. Nature Genet. 18, 136–141 (1998).

    Article  CAS  PubMed  Google Scholar 

  89. Tsai, P. T., Lee, R. A. & Wu, H. BMP4 acts upstream of FGF in modulating thymic stroma and regulating thymopoiesis. Blood 102, 3947–3953 (2003). This paper presents the first evidence linking the bone morphogenetic protein (Bmp)- and Fgf- signalling pathways in TECs, showing that Bmp signalling is upstream of Fgf signalling in fetal thymic organ cultures. Their results also indicate that Bmp4 regulates TEC sensitivity to Fgf signalling by Foxn1 regulation of Fgfr2-IIIb.

    Article  CAS  PubMed  Google Scholar 

  90. 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).

    Article  CAS  PubMed  Google Scholar 

  91. Colucci, F. et al. Dissecting NK cell development using a novel alymphoid mouse model: investigating the role of the c-abl proto-oncogene in murine NK cell differentiation. J. Immunol. 162, 2761–2765 (1999).

    CAS  PubMed  Google Scholar 

  92. Wang, J.- H. et al. Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity 5, 537–549 (1996).

    Article  CAS  PubMed  Google Scholar 

  93. Boehm, T., Scheu, S., Pfeffer, K. & Bleul, C. C. Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho–epithelial cross talk via LTβR. J. Exp. Med. 198, 757–769 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Itoi, M., Kawamoto, H., Katsura, Y. & Amagai, T. Two distinct steps of immigration of haematopoietic progenitors into the early thymus anlage. Int. Immunol. 13, 1203–1211 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Baxter, R. M. & Brissette, J. L. Role of the nude gene in epithelial terminal differentiation. J. Invest. Dermatol. 118, 303–309 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Su, D. M., Navarre, S., Oh, W. J., Condie, B. G. & Manley, N. R. A domain of Foxn1 required for crosstalk-dependent thymic epithelial cell differentiation. Nature Immunol. 4, 1128–1135 (2003). This paper reports a thymus-specific phenotype for a hypomorphic allele of Foxn1 that results in deletion of an amino-terminal domain of the protein. The TEC phenotype in these mice is consistent with a block at the thymocyte-dependent stage of TEC differentiation, and the resulting microenvironment causes blocks in thymocyte differentiation at the double-negative 1 and double-positive stages. These results show a tissue-specific requirement for the amino-terminal domain of Foxn1 in later stages of TEC differentiation.

    Article  CAS  Google Scholar 

  97. Markert, M. L. et al. Transplantation of thymus tissue in complete DiGeorge Syndrome. N. Engl. J. Med. 341, 1180–1189 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Hakim, F. T. & Gress, R. E. Reconstitution of thymic function after stem cell transplantation in humans. Curr. Opin. Hematol. 9, 490–496 (2002).

    Article  PubMed  Google Scholar 

  99. Reisner, Y. & Martelli, M. F. Tolerance induction by 'megadose' transplants of CD34+ stem cells: a new option for leukemia patients without an HLA-matched donor. Curr. Opin. Immunol. 12, 536–541 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. Reisner, Y. & Martelli, M. F. Stem cell escalation enables HLA-disparate haematopoietic transplants in leukaemia patients. Immunol. Today 20, 343–347 (1999).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

C.C.B. is supported by the Leukaemia Research Fund; N.R.M. is supported by the National Institutes of Health, the National Institute of Child Health and Human Development, and the National Institute of Allergy and Infectious Diseases. The authors are also supported by a Biomedical collaboration grant from the Wellcome Trust.

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  1. Institute for Stem Cell Research, The University of Edinburgh, King's Buildings, West Mains Road, Edinburgh, EH9 3JQ, UK

    C. Clare Blackburn

  2. Department of Genetics, B420A Life Sciences Building, University of Georgia, Athens, 30603, Georgia, USA

    Nancy R. Manley

Authors
  1. C. Clare Blackburn
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  2. Nancy R. Manley
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Correspondence to C. Clare Blackburn.

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DATABASES

LocusLink

Bmp4

CD4

CD8

CD25

CD44

Eya1

Fgf7

Fgf8

Fgf10

Fgfr2-IIIb

Foxn1

Gcm2

Hoxa3

Pax1

Pax9

Six1

Further information

Clare Blackburn's homepage

Nancy Manley's homepage

Glossary

STROMA

Cells that comprise the non-lymphocytic component of the thymus.

LINEAGE

Embryonic origin and fate of cells during normal development.

ENDODERM

The epithelial tube inside the embryo, which gives rise to the small and large intestines, stomach, organs such as the liver and pancreas, and glands, including the thyroid and parathyroid glands.

NEURAL CREST CELLS

Migratory cells derived from the neural tube ectoderm.

ECTODERM

The epithelial sheet that covers the outside of the embryo, which gives rise to skin and hair, for example.

NUDE

A recessive mutation in the forkhead box N1 (Foxn1) gene that causes hairlessness and congenital athymia in mice, rats and humans. Nude individuals lack T cells as a secondary effect of athymia; nude bone marrow is normal.

POTENCY

The differentiative capacity of cells, which might be more extensive than is apparent in normal development.

FETAL THYMIC ORGAN CULTURE

(FTOC). Experimental model for the analysis of T-cell development, typically based on in vitro culture of embryonic day 16.5 mouse fetal thymi.

REAGGREGATE FETAL THYMIC ORGAN CULTURE

(RFTOC). A variation of FTOC used to investigate the role of particular stromal subsets in T-cell development: stromal-cell types purified from fetal thymi are mixed with mesenchymal cells and T-cell progenitors, allowed to reaggregate either on a filter or in a hanging drop, and then cultured in vitro, as for FTOC, before analysis of T-cell development.

SPLOTCH MICE

Mice carrying a mutation in the transcription factor paired box gene 3 (Pax3), which have defects in derivatives of the somatic mesoderm and neural crest.

COMMON γ-CHAIN

(γc). A type I cytokine receptor chain that is shared by the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21. Mutant mice that lack both γc and recombination-activating gene 2 (Rag2) have a severe block in T-, B- and natural killer-cell development; thymocyte development in these mice is blocked at the CD25+ double-negative 2 stage.

IKAROS

This gene encodes a member of a family of zinc-finger transcription factors that are required for the development of all lymphoid lineages, as well as lymph nodes and Peyer's patches. Ikaros-null mutant fetuses lack B cells and T-cell precursors; few Ikaros-null cells enter the fetal thymus, and these fail to develop to the CD25+ double-negative 2 stage.

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Blackburn, C., Manley, N. Developing a new paradigm for thymus organogenesis. Nat Rev Immunol 4, 278–289 (2004). https://doi.org/10.1038/nri1331

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  • DOI: https://doi.org/10.1038/nri1331

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