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Thymus Organogenesis and Development of the Thymic Stroma

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Immunological Tolerance

Part of the book series: Methods in Molecular Biology™ ((MIMB,volume 380))

Abstract

T-cell development occurs principally in the thymus. Here, immature progenitor cells are guided through the differentiation and selection steps required to generate a complex T-cell repertoire that is both self-tolerant and has propensity to bind self major histocompatibility complex. These processes depend on an array of functionally distinct epithelial cell types within the thymic stroma, which have a common developmental origin in the pharyngeal endoderm. Here, we describe the structural and phenotypic attributes of the thymic stroma, and review current cellular and molecular understanding of thymus organogenesis.

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References

  1. Boyd, R. L., Tucek, C. L., Godfrey, D. L, et al. (1993) The thymic microenvironment. Immunol. Today 14, 445–459.

    Article  PubMed  CAS  Google Scholar 

  2. van Ewijk, W., Shores, E. W., and Singer, A. (1994) Crosstalk in the mouse thymus. Immunol. Today 15, 214–217.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  4. Lind, E. F., Prockop, S. E., Porritt, H. E., and Petrie, H. T. (2001) Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development. J. Exp. Med. 194, 127–134.

    Article  PubMed  CAS  Google Scholar 

  5. van de Wijngaert, F. P., Rademakers, L. H., Schuurman, H. J., de Weger, R. A., and Kater, L. (1983) Identification and in situ localization of the “thymic nurse cell” in man. J. Immunol. 130, 2348–2351.

    PubMed  Google Scholar 

  6. Brekelmans, P. and van Ewijk, W. (1990) Phenotypic characterization of murine thymic microenvironments. Semin. Immunol. 2, 13–24.

    PubMed  CAS  Google Scholar 

  7. Boyd, R. L., Wilson, T. J., Bean, A. G., Ward, H. A., and Gershwin, M. E. (1992) Phenotypic characterization of chicken thymic stromal elements. Dev. Immunol. 2, 51–66.

    Article  PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

  9. van de Wijngaert, F. P., Kendall, M. D., Schuurman, H. J., Rademakers, L. H., and Kater, L. (1984) Heterogeneity of epithelial cells in the human thymus. An ultrastructural study. Cell Tissue Res. 237, 227–237.

    Article  PubMed  Google Scholar 

  10. Wekerle, H. and Ketelsen, U. P. (1980) Thymic nurse cells-Ia-bearing epithelium involved in T-lymphocyte differentiation? Nature 283, 402–404.

    Article  PubMed  CAS  Google Scholar 

  11. Wekerle, H., Ketelsen, U. P., and Ernst, M. (1980) Thymic nurse cells. Lymphoepithelial cell complexes in murine thymuses: morphological and serological characterization. J. Exp. Med. 151, 925–944.

    Article  PubMed  CAS  Google Scholar 

  12. von Gaudecker, B., Steinmann, G. G., Hansmann, M. L., Harpprecht, J., Milicevic, N. M., and Muller-Hermelink, H. K. (1986) Immunohistochemical characterization of the thymic microenvironment. A light-microscopic and ultrastructural immunocytochemical study. Cell Tissue Res. 244, 403–412.

    Article  Google Scholar 

  13. Bofill, M., Janossy, G., Willcox, N., Chilosi, M., Trejdosiewicz, L. K., and Newsom-Davis, J. (1985) Microenvironments in the normal thymus and the thymus in myasthenia gravis. Am. J. Pathol. 119, 462–473.

    PubMed  CAS  Google Scholar 

  14. Surh, C. D., Gao, E. K., Kosaka, H., et al. (1992) Two subsets of epithelial cells in the thymic medulla. J. Exp. Med. 176, 495–505.

    Article  PubMed  CAS  Google Scholar 

  15. Farr, A. G. and Nakane, P. K. (1983) Cells bearing Ia antigens in the murine thymus. An ultrastructural study. Am. J. Pathol. 111, 88–97.

    PubMed  CAS  Google Scholar 

  16. Jenkinson, E. J., Van Ewijk, W., and Owen, J. J. (1981) Major histocompatibility complex antigen expression on the epithelium of the developing thymus in normal and nude mice. J. Exp. Med. 153, 280–292.

    Article  PubMed  CAS  Google Scholar 

  17. Klug, D. B., Carter, C., Crouch, E., Roop, D., Conti, C. J., and Richie, E. R. (1998) Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc. Natl. Acad. Sci. USA 95, 11,822–11,827.

    Article  PubMed  CAS  Google Scholar 

  18. Duijvestijn, A. M. and Hoefsmit, E. C. (1981) Ultrastructure of the rat thymus: the micro-environment of T-lymphocyte maturation. Cell Tissue Res. 218, 279–292.

    Article  PubMed  CAS  Google Scholar 

  19. Milicevic, N. M., Milicevic, Z., Colic, M., and Mujovic, S. (1987) Ultrastructural study of macrophages in the rat thymus, with special reference to the corticomedullary zone. J. Anat. 150, 89–98.

    PubMed  CAS  Google Scholar 

  20. Cardarelli, P. M., Crispe, I. N., and Pierschbacher, M. D. (1988) Preferential expression of fibronectin receptors on immature thymocytes. J. Cell Biol. 106, 2183–2190.

    Article  PubMed  CAS  Google Scholar 

  21. Cardarelli, P. M. and Pierschbacher, M. D. (1986) T-lymphocyte differentiation and the extracellular matrix: identification of a thymocyte subset that attaches specifically to fibronectin. Proc. Natl. Acad. Sci. USA 83, 2647–2651.

    Article  PubMed  CAS  Google Scholar 

  22. Schreiber, L., Eshel, I., Meilin, A., Sharabi, Y., and Shoham, J. (1991) Analysis of thymic stromal cell subpopulations grown in vitro on extracellular matrix in defined medium. III. Growth conditions of human thymic epithelial cells and immunomodulatory activities in their culture supernatant. Immunol. 74, 621–629.

    CAS  Google Scholar 

  23. Watt, S. M., Thomas, J. A., Murdoch, S. J., Kearney, L., Chang, S. E., and Bartek, J. (1991) Human thymic epithelial cells are frequently transformed by retro viral vectors encoding simian virus 40. Cell. Immunol. 138, 456–472.

    Article  PubMed  CAS  Google Scholar 

  24. Anderson, G., Anderson, K. L., Tchilian, E. Z., Owen, J. J., and Jenkinson, E. J. (1997) Fibroblast dependency during early thymocyte development maps to the CD25+ CD44+ stage and involves interactions with fibroblast matrix molecules. Eur. J. Immunol. 27, 1200–1206.

    Article  PubMed  CAS  Google Scholar 

  25. Boyd, R. L. and Hugo, P. (1991) Towards an integrated view of thymopoiesis. Immunol. Today 12, 71–79.

    Article  PubMed  CAS  Google Scholar 

  26. Savino, W., Villa-Verde, D. M. and Lannes-Vieira, J. (1993) Extracellular matrix proteins in intrathymic T-cell migration and differentiation? Immunol. Today 14, 158–161.

    Article  PubMed  CAS  Google Scholar 

  27. Watt, S. M., Thomas, J. A., Edwards, A. J., Murdoch, S. J., and Horton, M. A. (1992) Adhesion receptors are differentially expressed on developing thymocytes and epithelium in human thymus. Exp. Hematol. 20, 1101–1111.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  31. Moore, N. C., Anderson, G., Smith, C. A., Owen, J. J., and Jenkinson, E. J. (1993) Analysis of cytokine gene expression in subpopulations of freshly isolated thymocytes and thymic stromal cells using semiquantitative polymerase chain reaction. Eur. J. Immunol. 23, 922–927.

    Article  PubMed  CAS  Google Scholar 

  32. Hare, K. J., Jenkinson, E. J., and Anderson, G. (2000) An essential role for the IL-7 receptor during intrathymic expansion of the positively selected neonatal T cell repertoire. J. Immunol. 165, 2410–2414.

    PubMed  CAS  Google Scholar 

  33. Zamisch, M., Moore-Scott, B., Su, D. M., Lucas, P. J., Manley, N., and Richie, E. R. (2005) Ontogeny and regulation of IL-7-expressing thymic epithelial cells. J. Immunol. 17 4, 60–67.

    Google Scholar 

  34. von Freeden-Jeffry, U., Vieira, P., Lucian, L. A., McNeil, T., Burdach, S. E., and Murray, R. (1995) Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J. Exp. Med. 181, 1519–1526.

    Article  Google Scholar 

  35. Crompton, T., Outram, S. V., Buckland, J., and Owen, M. J. (1998) Distinct roles of the interleukin-7 receptor alpha chain in fetal and adult thymocyte development revealed by analysis of interleukin-7 receptor alpha-deficient mice. Eur. J. Immunol. 28, 1859–1866.

    Article  PubMed  CAS  Google Scholar 

  36. Zuniga-Pflucker, J. C., Di, J., and Lenardo, M. J. (1995) Requirement for TNF-alpha and IL-1 alpha in fetal thymocyte commitment and differentiation. Science 268, 1906–1909.

    Article  PubMed  CAS  Google Scholar 

  37. Savino, W., Mendes-da-Cruz, D. A., Silva, J. S., Dardenne, M., and Cotta-de-Almeida, V. (2002) Intrathymic T-cell migration: a combinatorial interplay of extracellular matrix and chemokines? Trends Immunol. 23, 305–313.

    Article  PubMed  CAS  Google Scholar 

  38. Misslitz, A., Pabst, O., Hintzen, G., Ohl, L., Kremmer, E., Petrie, H. T., and Forster, R. (2004) Thymic T cell development and progenitor localization depend on CCR7. J. Exp. Med. 200, 481–491.

    Article  PubMed  CAS  Google Scholar 

  39. Benz, C., Heinzel, K., and Bleul, C. C. (2004) 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.

    Article  PubMed  CAS  Google Scholar 

  40. Cosgrove, D., Chan, S. H., Waltzinger, C., Benoist, C., and Mathis, D. (1992) The thymic compartment responsible for positive selection of CD4+ T cells. Int. Immunol. 4, 707–710.

    Article  PubMed  CAS  Google Scholar 

  41. Benoist, C. and Mathis, D. (1989) Positive selection of the T cell repertoire: where and when does it occur? Cell 58, 1027–1033.

    Article  PubMed  CAS  Google Scholar 

  42. Berg, L. J., Pullen, A. M., Fazekas de St. Groth, B., Mathis, D., Benoist, C., and Davis, M. M. (1989) Antigen/MHC-specific T cells are preferentially exported from the thymus in the presence of their MHC ligand. Cell 58, 1035–1046.

    Article  PubMed  CAS  Google Scholar 

  43. Wilson, A., MacDonald, H. R., and Radtke, F. (2001) Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus. J. Exp. Med. 194, 1003–1012.

    Article  PubMed  CAS  Google Scholar 

  44. Radtke, F., Wilson, A., Stark, G., et al. (1999) Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10, 547–558.

    Article  PubMed  CAS  Google Scholar 

  45. Harman, B. C., Jenkinson, E. J., and Anderson, G. (2003) Entry into the thymic microenvironment triggers Notch activation in the earliest migrant T cell progenitors. J. Immunol. 170, 1299–1303.

    PubMed  CAS  Google Scholar 

  46. Anderson, G., Pongracz, J., Parnell, S., and Jenkinson, E. J. (2001) Notch ligand-bearing thymic epithelial cells initiate and sustain Notch signaling in thymocytes independently of T cell receptor signaling. Eur. J. Immunol. 31, 3349–3354.

    Article  PubMed  CAS  Google Scholar 

  47. Allman, D., Karnell, F. G., Punt, J. A., et al. (2001) Separation of Notch1 promoted lineage commitment and expansion/transformation in developing T cells. J. Exp. Med. 194, 99–106.

    Article  PubMed  CAS  Google Scholar 

  48. Huang, E. Y., Gallegos, A. M., Richards, S. M., Lehar, S. M., and Bevan, M. J. (2003) Surface expression of Notch1 on thymocytes: correlation with the double-negative to double-positive transition. J. Immunol. 171, 2296–2304.

    PubMed  CAS  Google Scholar 

  49. Deftos, M. L., Huang, E., Ojala, E. W., Forbush, K. A., and Bevan, M. J. (2000) Notch1 signaling promotes the maturation of CD4 and CD8 SP thymocytes. Immunity 13, 73–84.

    Article  PubMed  CAS  Google Scholar 

  50. Deftos, M. L., He, Y. W., Ojala, E. W., and Bevan, M. J. (1998) Correlating notch signaling with thymocyte maturation. Immunity 9, 777–786.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  52. Gotter, J., Brors, B., Hergenhahn, M., and Kyewski, B. (2004) Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters. J. Exp. Med. 199, 155–166.

    Article  PubMed  CAS  Google Scholar 

  53. 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 LTβR. J. Exp. Med. 198, 757–769.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  55. Chin, R. K., Lo, J. C., Kim, O., et al. (2003) Lymphotoxin pathway directs thymic Aire expression. Nat. Immunol. 4, 1121–1127.

    Article  PubMed  CAS  Google Scholar 

  56. Gotter, J. and Kyewski, B. (2004) Regulating self-tolerance by deregulating gene expression. Curr. Opin. Immunol. 16, 741–745.

    Article  PubMed  CAS  Google Scholar 

  57. Liston, A., Lesage, S., Wilson, J., Peltonen, L., and Goodnow, C. C. (2003) Aire regulates negative selection of organ-specific T cells. Nat. Immunol. 4, 350–354.

    Article  PubMed  CAS  Google Scholar 

  58. Villasenor, J., Benoist, C., and Mathis, D. (2005) AIRE and APECED: molecular insights into an autoimmune disease. Immunol. Rev. 204, 156–164.

    Article  PubMed  CAS  Google Scholar 

  59. Vogel, A., Liermann, H., Harms, A., Strassburg, C. P., Manns, M. P., and Obermayer-Straub, P. (2001) Autoimmune regulator AIRE: evidence for genetic differences between autoimmune hepatitis and hepatitis as part of the autoimmune poly glandular syndrome type 1. Hepatol. 33, 1047–1052.

    Article  CAS  Google Scholar 

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

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  62. Owen, J. J. and Ritter, M. A. (1969) Tissue interaction in the development of thymus lymphocytes. J. Exp. Med. 129, 431–442.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  64. Jotereau, F., Heuze, F., Salomon-Vie, V., and Gascan, H. (1987) Cell kinetics in the fetal mouse thymus: precursor cell input, proliferation, and emigration. J. Immunol. 138, 1026–1030.

    PubMed  CAS  Google Scholar 

  65. Douagi, I., Andre, I., Ferraz, J. C., and Cumano, A. (2000) Characterization of T cell precursor activity in the murine fetal thymus: evidence for an input of T cell precursors between days 12 and 14 of gestation. Eur. J. Immunol. 30, 2201–2210.

    PubMed  CAS  Google Scholar 

  66. Bennett, A. R., Farley, A., Blair, N. R, Gordon, J., Sharp, L., and Blackburn, C. C. (2002) Identification and characterization of thymic epithelial progenitor cells. Immunity 16, 803–814.

    Article  PubMed  CAS  Google Scholar 

  67. Klug, D. B., Carter, C., Gimenez-Conti, I. B., and Richie, E. R. (2002) Cutting edge: thymocyte-independent and thymocyte-dependent phases of epithelial patterning in the fetal thymus. J. Immunol. 169, 2842–2845.

    PubMed  CAS  Google Scholar 

  68. Jenkinson, W. E., Rossi, S. W., Jenkinson, E. J., and Anderson, G. (2005) Development of functional thymic epithelial cells occurs independently of lymphostromal interactions. Mech. Dev. 122, 1294–1299.

    Article  PubMed  CAS  Google Scholar 

  69. Van Vliet, E., Melis, M., and Van Ewijk, W. (1984) Monoclonal antibodies to stromal cell types of the mouse thymus. Eur. J. Immunol. 14, 524–529.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  71. Le Douarin, N. M. and Jotereau, R V. (1975) Tracing of cells of the avian thymus through embryonic life in interspecific chimeras. J. Exp. Med. 142, 17–40.

    Article  PubMed  Google Scholar 

  72. Gordon, J., Wilson, V. A., Blair, N. R. et al. (2004) Functional evidence for a single endodermal origin for the thymic epithelium. Nat. Immunol. 5, 546–553.

    Article  PubMed  CAS  Google Scholar 

  73. Blackburn, C. C. and Manley, N. R. (2004) Developing a new paradigm for thymus organogenesis. Nat. Rev. Immunol. 4, 278–289.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  75. Schluep, M., Willcox, N., Ritter, M. A., Newsom-Davis, J., Larche, M., and Brown, A. N. (1988) Myasthenia gravis thymus: clinical, histological and culture correlations. J. Autoimmun. 1, 445–467.

    Article  PubMed  CAS  Google Scholar 

  76. Blackburn, C. C., Augustine, C. L., Li, R., et al. (1996) The nu gene acts cell-autonomously and is required for differentiation of thymic epithelial progenitors. Proc. Natl. Acad. Sci. USA 93, 5742–5746.

    Article  PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  79. Gill, J., Malin, M., Hollander, G. A., and Boyd, R. (2002) Generation of a com-plete thymic microenvironment by MTS24(+) thymic epithelial cells. Nat. Immunol. 3, 635–642.

    Article  PubMed  CAS  Google Scholar 

  80. 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.

    Article  PubMed  CAS  Google Scholar 

  81. Klug, D. B., Crouch, E., Carter, C., Coghlan, L., Conti, C. J., and Richie, E. R. (2000) Transgenic expression of cyclin D1 in thymic epithelial precursors promotes epithelial andT cell development. J. Immunol. 164, 1881–1888.

    PubMed  CAS  Google Scholar 

  82. Norris, E. H. (1938) The morphogenesis and histogenesis of the thymus gland in man: in which the origin of the Hassall’s corpuscle of the human thymus is discovered. Contr. Embryol. Carnegie Instn. 27, 191–207.

    Google Scholar 

  83. Weller, G. L. (1933) Development of the thyroid, parathyroid and thymus glands in man. Cont. Embryol. 141, 95–138.

    Google Scholar 

  84. Van Dyke, J. H. (1941) On the origin of accessory thymus tissue, thymus IV: the occurrence in man. Anat. Rec. 79, 179–209.

    Article  Google Scholar 

  85. Lampert, I. A. and Ritter, M. A. (1988) The origin of the diverse epithelial cells of the thymus: is there a common stem cell? In: Thymus Update, (Kendall, M. D. and Ritter, M. A., eds.), Harwood Academic, UK, pp. 5–25.

    Google Scholar 

  86. Lobach, D. F. and Haynes, B. F. (1986) Ontogeny of the human thumus during fetal development. J. Clin. Immunol. 7, 81–97.

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  89. 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.

    PubMed  CAS  Google Scholar 

  90. Shinohara, T. and Honjo, T. (1997) Studies in vitro on the mechanism of the epithelial/mesenchymal interaction in the early fetal thymus. Eur. J. Immunol. 27, 522–529.

    Article  PubMed  CAS  Google Scholar 

  91. Anderson, G. and Jenkinson, E. J. (2001) Lymphostromal interactions in thymic development and function. Nat. Rev. Immunol. 1, 31–40.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  93. Farr, A., Nelson, A., Hosier, S., and Kim, A. (1993) A novel cytokine-responsive cell surface glycoprotein defines a subset of medullary thymic epithelium in situ. J. Immunol. 150, 1160–1171.

    PubMed  CAS  Google Scholar 

  94. Ropke, C. and Elbroend, J. (1992) Human thymic epithelial cells in serum-free culture: nature and effects on thymocyte cell lines. Dev. Immunol. 2, 111–121.

    Article  PubMed  CAS  Google Scholar 

  95. Galy, A. H. and Spits, H. (1992) CD40 is functionally expressed on human thymic epithelial cells. J. Immunol. 149, 775–782.

    PubMed  CAS  Google Scholar 

  96. Colic, M., Pejnovic, N., Kataranovski, M., Popovic, L., Gassic, S., and Dujic, A. (1992) Interferon gamma alters the phenotype of rat thymic epithelial cells in culture and increases interleukin-6 production. Dev. Immunol. 2, 151–160.

    Article  PubMed  CAS  Google Scholar 

  97. Montgomery, R. A. and Dallman, M. J. (1991) Analysis of cytokine gene expression during fetal thymic ontogeny using the polymerase chain reaction. J. Immunol. 147, 554–560.

    PubMed  CAS  Google Scholar 

  98. Le, P. T., Lazorick, S., Whichard, L. P., Haynes, B. E, and Singer, K. H. (1991) Regulation of cytokine production in the human thymus: epidermal growth factor and transforming growth factor alpha regulate mRNA levels of interleukin 1 alpha (IL-1 alpha), IL-1 beta, and IL-6 in human thymic epithelial cells at a posttranscriptional level. J. Exp. Med. 174, 1147–1157.

    Article  PubMed  CAS  Google Scholar 

  99. Galy, A. H. and Spits, H. (1991) IL-1, IL-4, and IFN-gamma differentially regulate cytokine production and cell surface molecule expression in cultured human thymic epithelial cells. J. Immunol. 147, 3823–3830.

    PubMed  CAS  Google Scholar 

  100. Dalloul, A. H., Arock, M., Fourcade, C., et al. (1991) Human thymic epithelial cells produce interleukin-3. Blood 77, 69–74.

    PubMed  CAS  Google Scholar 

  101. Colic, M., Pejnovic, N., Kataranovski, M., Stojanovic, N., Terzic, T., and Dujic, A. (1991) Rat thymic epithelial cells in culture constitutively secrete IL-1 and IL-6. Int. Immunol. 3, 1165–1174.

    Article  PubMed  CAS  Google Scholar 

  102. Cohen-Kaminsky, S., Delattre, R. M., Devergne, O., et al. (1991) Synergistic induction of interleukin-6 production and gene expression in human thymic epithelial cells by LPS and cytokines. Cell. Immunol. 138, 79–93.

    Article  PubMed  CAS  Google Scholar 

  103. Barcena, A., Sanchez, M. J., de la Pompa, J. L., Toribio, M. L., Kroemer, G., and Martinez, A. C. (1991) Involvement of the interleukin 4 pathway in the generation of functional gamma delta T cells from human pro-T cells. Proc. Natl. Acad. Sci. USA 88, 7689–7693.

    Article  PubMed  CAS  Google Scholar 

  104. Le, P. T., Lazorick, S., Whichard, L. P., et al. (1990) Human thymic epithelial cells produce IL-6, granulocyte-monocyte-CSF, and leukemia inhibitory factor. J. Immunol. 145, 3310–3315.

    PubMed  CAS  Google Scholar 

  105. Erickson, M., Morkowski, S., Lehar, S., et al. (2002) Regulation of thymic epithelium by keratinocyte growth factor. Blood 100, 3269–3278.

    Article  PubMed  CAS  Google Scholar 

  106. 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.

    Article  PubMed  CAS  Google Scholar 

  107. Hu, T., Yamagishi, H., Maeda, J., McAnally, J., Yamagishi, C., and Srivastava, D. (2004) Tbx1 regulates fibroblast growth factors in the anterior heart field through a reinforcing autoregulatory loop involving forkhead transcription factors. Development 131, 5491–5502.

    Article  PubMed  CAS  Google Scholar 

  108. Xu, H., Morishima, M., Wylie, J. N., et al. (2004) Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract. Development 131, 3217–3227.

    Article  PubMed  CAS  Google Scholar 

  109. Chapman, D. L., Garvey, N., Hancock, S., et al. (1996) Expression of the T-box family genes, Tbx1-Tbx5, during early mouse development. Dev. Dyn. 206, 379–390.

    Article  PubMed  CAS  Google Scholar 

  110. Lindsay, E. A., Botta, A., Jurecic, V., et al. (1999) Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature 401, 379–383.

    PubMed  CAS  Google Scholar 

  111. Scambler, P. J. (2000) The 22q11 deletion syndromes. Hum. Mol. Genet. 9, 2421–2426.

    Article  PubMed  CAS  Google Scholar 

  112. Taddei, I., Morishima, M., Huynh, T., and Lindsay, E. A. (2001) Genetic factors are major determinants of phenotypic variability in a mouse model of the DiGeorge/del22q1 1 syndromes. Proc. Natl. Acad. Sci. USA 98, 11,428–11,431.

    Article  PubMed  CAS  Google Scholar 

  113. Paylor, R., McIlwain, K. L., McAninch, R., et al. (2001) Mice deleted for the DiGeorge/velocardiofacial syndrome region show abnormal sensorimotor gating and learning and memory impairments. Hum. Mol. Genet. 10, 2645–2650.

    Article  PubMed  CAS  Google Scholar 

  114. Jerome, L. A. and Papaioannou, V. E. (2001) DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat. Genet. 27, 286–291.

    Article  PubMed  CAS  Google Scholar 

  115. Lindsay, E. A., Vitelli, F., Su, H., et al. (2001) Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410, 97–101.

    Article  PubMed  CAS  Google Scholar 

  116. Merscher, S., Funke, B., Epstein, J. A., et al. (2001) TBX1 is responsible for car diovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 104, 619–629.

    Article  PubMed  CAS  Google Scholar 

  117. Xu, H., Cerrato F, and Baldini, A. (2005) Timed mutation and cell-fate mapping reveal reiterated roles of Tbx1 during embryogenesis, and a crucial function during segmentation of the pharyngeal system via regulation of endoderm expansion. Development 132, 4387–4395.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  119. Manley, N. R. and Capecchi, M. R. (1998) Hox group 3 paralogs regulate the development and migration of the thymus, thyroid, and parathyroid glands. Dev. Biol. 195, 1–15.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  121. Neubuser, A., Koseki, H., and Balling, R. (1995) Characterization and developmental expression of Pax9, a paired-box-containing gene related to Pax1. Dev. Biol. 170, 701–716.

    Article  PubMed  CAS  Google Scholar 

  122. Wallin, J., Eibel, H., Neubuser, A., Wilting, J., Koseki, H., and Balling, R. (1996) Pax1 is expressed during development of the thymus epithelium and is required for normal T-cell maturation. Development 122, 23–30.

    PubMed  CAS  Google Scholar 

  123. Su, D. M. and Manley, N. R. (2000) Hoxa3 and pax1 transcription factors regulate the ability of fetal thymic epithelial cells to promote thymocyte development. J. Immunol. 164, 5753–5760.

    PubMed  CAS  Google Scholar 

  124. 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.

    Article  PubMed  CAS  Google Scholar 

  125. Hetzer-Egger, C., Schorpp, M., Haas-Assenbaum, A., Balling, R., Peters, H., and Boehm, T. (2002) Thymopoiesis requires Pax9 function in thymic epithelial cells. Eur. J. Immunol. 32, 1175–1181.

    Article  PubMed  CAS  Google Scholar 

  126. Bonini, N. M., Leiserson, W. M., and Benzer, S. (1993) The eyes absent gene: genetic control of cell survival and differentiation in the developing Drosophila eye. Cell 72, 379–395.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  128. Xu, P. X., Woo, I., Her, H., Beier, D. R., and Maas, R. L. (1997) Mouse Eya homologues of the Drosophila eyes absent gene require Pax6 for expression in lens and nasal placode. Development 124, 219–231.

    PubMed  CAS  Google Scholar 

  129. Oliver, G., Mailhos, A., Wehr, R., Copeland, N. G., Jenkins, N. A., and Gruss, P. (1995) Six3, a murine homologue of the sine oculis gene, demarcates the most anterior border of the developing neural plate and is expressed during eye development. Development 121, 4045–4055.

    PubMed  CAS  Google Scholar 

  130. Li, X., Oghi, K. A., Zhang, J., et al. (2003) Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature 426, 247–254.

    Article  PubMed  CAS  Google Scholar 

  131. Pignoni, F., Hu, B., Zavitz, K. H., Xiao, J., Garrity, P. A., and Zipursky, S. L. (1997) The eye-specification proteins So and Eya form a complex and regulate multiple steps in Drosophila eye development. Cell 91, 881–891.

    Article  PubMed  CAS  Google Scholar 

  132. Conway, S. J., Bundy, J., Chen, J., Dickman, E., Rogers, R., and Will, B. M. (2000) Decreased neural crest stem cell expansion is responsible for the conotruncal heart defects within the splotch (Sp(2H))/Pax3 mouse mutant. Cardiovasc. Res. 47, 314–328.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  134. Machado, A. E, Martin, L. J., and Collins, M. D. (2001) Pax3 and the splotch mutations: structure, function, and relationship to teratogenesis, including gene-chemical interactions. Curr. Pharm. Des. 7, 751–785.

    Article  PubMed  CAS  Google Scholar 

  135. Boehm, T., Bleul, C. C., and Schorpp, M. (2003) Genetic dissection of thymus development in mouse and zebrafish. Immunol. Rev. 195, 15–27.

    Article  PubMed  CAS  Google Scholar 

  136. Cordier, A. C. (1974) Ultrastructure of the thymus in “Nude” mice. J. Ultrastruct. Res. 47, 26–40.

    Article  PubMed  CAS  Google Scholar 

  137. Gordon, J., Bennett, A. R., Blackburn, C. C., and Manley, N. R. (2001) Gcm2 and Foxn1 mark early parathyroid-and thymus-specific domains in the developing third pharyngeal pouch. Mech. Dev. 103, 141–143.

    Article  PubMed  CAS  Google Scholar 

  138. 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.

    Article  PubMed  CAS  Google Scholar 

  139. Balciunaite, G., Keller, M. P., Balciunaite, E., et al. (2002) Wnt glycoproteins regulate the expression of FoxN1, the gene defective in nude mice. Nat. Immunol. 3, 1102–1108.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  142. Gunther, T., Chen, Z. E, Kim, J., et al. (2000) Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. Nature 406, 199–203.

    Article  PubMed  CAS  Google Scholar 

  143. Brissette, J. L., Li, J., Kamimura, J., Lee, D., and Dotto, G. P. (1996) The product of the mouse nude locus, Whn, regulates the balance between epithelial cell growth and differentiation. Genes Dev. 10, 2212–2221.

    Article  PubMed  CAS  Google Scholar 

  144. 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 andAkt. J. Cell Sci. 117, 4157–4168.

    Article  PubMed  CAS  Google Scholar 

  145. Bleul, C. C. and Boehm, T. (2001) Laser capture microdissection-based expression profiling identifies PD1-ligand as a target of the nude locus gene product. Eur. J. Immunol. 31, 2497–2503.

    Article  PubMed  CAS  Google Scholar 

  146. 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.

    Article  PubMed  CAS  Google Scholar 

  147. Nishimura, H., Agata, Y., Kawasaki, A., et al. (1996) Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4-CD8-) thymocytes. Int. Immunol. 8, 773–780.

    Article  PubMed  CAS  Google Scholar 

  148. Nishimura, H., Honjo, T., and Minato, N. (2000) Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. J. Exp. Med. 191, 891–898.

    Article  PubMed  CAS  Google Scholar 

  149. Patel, S. R., Gordon, J., Mahbub, F., Blackburn, C. C., and Manley, N. (2006) Bmp4 and Noggin expression during early thymus and parathyroid organogenesis. Gene Expr Patterns 6(8), 794–799.

    Article  PubMed  CAS  Google Scholar 

  150. 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.

    Article  PubMed  CAS  Google Scholar 

  151. Bleul, C. C. and Boehm, T. (2005) BMP signaling is required for normal thymus development. J. Immunol. 175, 5213–5221.

    PubMed  CAS  Google Scholar 

  152. Abu-Issa, R., Smyth, G., Smoak, I., Yamamura, K., and Meyers, E. N. (2002) Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse. Development 129, 4613–4625.

    PubMed  CAS  Google Scholar 

  153. Frank, D. U., Fotheringham, L. K., Brewer, J. A., et al. (2002) An Fgf8 mouse mutant phenocopies human 22q1 1 deletion syndrome. Development 129, 4591–4603.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  155. Mitchell, P. J., Timmons, P. M., Hebert, J. M., Rigby, P. W., and Tjian, R. (1991) Transcription factor AP-2 is expressed in neural crest cell lineages during mouse embryogenesis. Genes Dev. 5, 105–119.

    Article  PubMed  CAS  Google Scholar 

  156. Dencker, L., Annerwall, E., Busch, C., and Eriksson, U. (1990) Localization of specific retinoid-binding sites and expression of cellular retinoic-acid-binding protein (CRABP) in the early mouse embryo. Development 110, 343–352.

    PubMed  CAS  Google Scholar 

  157. Macatee, T. L., Hammond, B. P., Arenkiel, B. R., Francis, L., Frank, D. U., and Moon, A. M. (2003) Ablation of specific expression domains reveals discrete functions of ectoderm-and endoderm-derived FGF8 during cardiovascular and pharyngeal development. Development 130, 6361–6374.

    Article  PubMed  CAS  Google Scholar 

  158. 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.

    Article  PubMed  CAS  Google Scholar 

  159. Campbell, J. J., Pan, J., and Butcher, E. C. (1999) Cutting edge: developmental switches in chemokine responses during T cell maturation. J. Immunol. 163, 2353–2357.

    PubMed  CAS  Google Scholar 

  160. 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.

    PubMed  CAS  Google Scholar 

  161. Ghyselinck, N. B., Dupe, V., Dierich, A., et al. (1997) Role of the retinoic acid receptor beta (RARbeta) during mouse development. Int. J. Dev. Biol. 41, 425–447.

    PubMed  CAS  Google Scholar 

  162. Kanariou, M., Huby, R., Ladyman, H., et al. (1989) Immunosuppression with cyclosporin A alters the thymic microenvironment. Clin. Exp. Immunol. 78, 263–270.

    PubMed  CAS  Google Scholar 

  163. Imami, N., Ladyman, H. M., Spanopoulou, E., and Ritter, M. A. (1992) A novel adhesion molecule in the murine thymic microenvironment: functional and biochemical analysis. Dev. Immunol. 2, 161–173.

    Article  PubMed  CAS  Google Scholar 

  164. Rouse, R. V., Bolin, L. M., Bender, J. R., and Kyewski, B. A. (1988) Monoclonal antibodies reactive with subsets of mouse and human thymic epithelial cells. J. Histochem. Cytochem. 36, 1511–1517.

    Article  PubMed  CAS  Google Scholar 

  165. Vicari, A., Abehsira-Amar, O., Papiernik, M., Boyd, R. L., and Tucek, C. L. (1994) MTS-32 monoclonal antibody defines CD4+8-thymocyte subsets that differ in their maturation level, lymphokine secretion, and selection patterns. J. Immunol. 152, 2207–2213.

    PubMed  CAS  Google Scholar 

  166. MacNeil, I., Kennedy, J., Godfrey, D. L, et al. (1993) Isolation of a cDNA encoding thymic shared antigen-1. A new member of the Ly6 family with a possible role in T cell development. J. Immunol. 151, 6913–6923.

    PubMed  CAS  Google Scholar 

  167. Randle, E. S., Waanders, G. A., Masciantonio, M., Godfrey, D.I., and Boyd, R. L. (1993) A lymphostromal molecule, thymic shared Ag-1, regulates early thymocyte development in fetal thymus organ culture. J. Immunol. 151, 6027–6035.

    PubMed  CAS  Google Scholar 

  168. Ivanov, V. and Ceredig, R. (1992) Transcription factors in mouse fetal thymus development. Int. Immunol. 4, 729–737.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Institute for Stem Cell Research, University of Edinburgh, Edinburgh, UK

    Craig S. Nowell, Alison M. Farley & C. Clare Blackburn

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  1. Craig S. Nowell
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  2. Alison M. Farley
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  1. Sir William Dunn School of Pathology, University of Oxford, Oxford, UK

    Paul J. Fairchild

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Nowell, C.S., Farley, A.M., Blackburn, C.C. (2007). Thymus Organogenesis and Development of the Thymic Stroma. In: Fairchild, P.J. (eds) Immunological Tolerance. Methods in Molecular Biology™, vol 380. Humana Press. https://doi.org/10.1007/978-1-59745-395-0_8

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