Toward Understanding How the Immune System Establishes a Diverse Yet Self-Tolerant T-Cell Repertoire: Stepwise Roles of Thymic Microenvironments

  • Takeshi Nitta
  • Yousuke Takahama
Conference paper

The thymus is an organ that supports the development and repertoire formation of T lymphocytes (1). Thymic parenchyma consists of leukocytic cells called thymocytes, the majority of which belong to the T-lymphoid lineage, and various stromal cells including thymic epithelial cells (TEC) (2). Thymic stromal cells provide multiple signals to support manifold processes of thymocyte development that are essential for the supply of circulating T lymphocytes (3). In response to these signals, developing thy-mocytes undergo proliferation, differentiation, and relocation to generate mature T lymphocytes that carry a diverse yet self-tolerant repertoire of T-cell antigen receptors (TCR) (4). These steps of T-lymphocyte development take place in anatomically discrete regions of the thymus where a variety of specialized stromal cells are localized (5).

T lymphocytes arise from hematopoietic stem cell-derived T-lymphoid progenitor cells that migrate to the thymus (6). Most immature hematopoietic cells that have just entered the thymus lack the expression of CD4 and CD8 and therefore belong to CD4/CD8 double-negative (DN) thymocytes (7, 8). The development of DN thymocytes is associated with the dynamic relocation of the cells in thymic parenchyma; T-lymphoid progenitor cells in adult mouse thymus are mostly localized in the corticomedullary junction, the area between deep cortex and medulla (9), whereas thymocytes migrate toward the capsular region of the thymus during differentiation and develop into CD4/CD8 double-positive (DP) thymocytes (10). DP thymocytes expressing TCR on the cell surface are localized in the cortex. DP thymocytes move actively within the cortical microenvironment (11, 12), probably seeking TCR interaction with major histocompatibility complex (MHC)-encoded molecules that are associated with self-peptides. Cortical DP thymocytes that interact via their TCR with the self-peptide—complex are selected for survival or death depending on the avidity of the interaction (13, 14). DP thymocytes that receive TCR signals with ligand interactions of weak avidity and nonextensive aggregation are induced to survive and differentiate into mature thymocytes, the process referred to as positive selection (15, 16). By contrast, DP thymocytes that receive TCR signals with ligand interactions of strong avidity and extensive aggregation are destined to die (17, 18), a process referred to as negative selection. During positive selection, the differential kinetics of TCR—ligand interactions determines cell lineage to become either CD4+ CD8 or CD4 CD8+ single-positive (SP) thymocytes (19). Positively selected thymocytes relocate to thymic medulla, where they further interact with self-peptides displayed in the medullary microenvironment (20). Medullary TEC (mTEC) express a diverse set of genes representing peripheral tissues (21), thereby contributing to the establishment of self-tolerance in thymic medulla. A nuclear factor called autoimmune regulator (AIRE) participates in this promiscuous gene expression in mTEC (22). Consequently, a diverse yet self-tolerant TCR repertoire is formed in the thymus, and mature T lymphocytes with such a TCR repertoire are released to the circulation. Thus, T-cell repertoire formation consists of stepwise fate determinations of thymocyte development in different thymic microenvironments. The dynamic relocation of developing thymocytes within thymic microenvironments is crucial for T-cell repertoire selection.


Major Histocompatibility Complex Major Histocompatibility Complex Class Thymic Epithelial Cell Thymocyte Development CCR7 Ligand 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Miller, J. F. A. P. (1961) Immunological function of the thymus. Lancet 2:748–749.PubMedCrossRefGoogle Scholar
  2. 2.
    Sainte-Marie, G. and Leblond, C. P. (1964) Cytologic features and cellular migration in the cortex and medulla of thymus in the young adult rat. Blood 23:275–299.PubMedGoogle Scholar
  3. 3.
    Kingston, R., Jenkinson, E. J., and Owen, J. J. (1985) A single stem cell can recolonize an embryonic thymus, producing phenotypically distinct T-cell populations. Nature (Lond) 317:811–813.CrossRefGoogle Scholar
  4. 4.
    von Boehmer, H. (1988) The developmental biology of T lymphocytes. Annu. Rev. Immunol. 6:309–326CrossRefGoogle Scholar
  5. 5.
    Jenkinson, E. J., Owen, J. J., and Aspinall, R. (1980). Lymphocyte differentiation and major histocompatibility complex antigen expression in the embryonic thymus. Nature (Lond) 284:177–179.CrossRefGoogle Scholar
  6. 6.
    Le Douarin, N. M. and Jotereau, F. V. (1975) Tracing of cells of the avian thymus through embryonic life in interspecific chimeras. J. Exp. Med. 142:17–40.PubMedCrossRefGoogle Scholar
  7. 7.
    Bhandoola, A., Sambandam, A., Allman, D., Meraz, A., and Schwarz, B. (2003) Early T lineage progenitors: new insights, but old questions remain. J. Immunol. 171:5653–5658.PubMedGoogle Scholar
  8. 8.
    Scollay, R., Wilson, A., D'Amico, A., Kelly, K., Egerton, M., Pearse, M., Wu, L., and Shortman, K. (1988) Developmental status and reconstitution potential of subpopulations of murine thymocytes. Immunol. Rev. 104:81–120.PubMedCrossRefGoogle Scholar
  9. 9.
    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.PubMedCrossRefGoogle Scholar
  10. 10.
    Wilson, A., Petrie, H. T., Scollay, R. and Shortman, K. (1989). The acquisition of CD4 and CD8 during the differentiation of early thymocytes in short-term culture. Int. Immunol. 1:605–612.PubMedCrossRefGoogle Scholar
  11. 11.
    Witt, C. M., Raychaudhuri, S., Schaefer, B., Chakraborty, A. K., and Robey, E. A. (2005) Directed migration of positively selected thymocytes visualized in real time. PLoS Biol. 3:e160.PubMedCrossRefGoogle Scholar
  12. 12.
    Li, J., Iwanami, N., Hoa, V. Q., Furutani-Seiki, M., and Takahama, Y. (2007) Noninvasive intravital imaging of thymocyte dynamics in medaka. J. Immunol. 179:1605–1615.PubMedGoogle Scholar
  13. 13.
    von Boehmer, H. (1994) Positive selection of lymphocytes. Cell 76:219–228.CrossRefGoogle Scholar
  14. 14.
    Allen, P. M. (1994) Peptides in positive and negative selection: a delicate balance. Cell 76:593–596.PubMedCrossRefGoogle Scholar
  15. 15.
    Ashton-Rickardt, P. G., Van Kaer, L., Schumacher, T. N., Ploegh, H. L., and Tonegawa, S. (1993) Peptide contributes to the specificity of positive selection of CD8+ T cells in the thymus. Cell 73:1041–1049.PubMedCrossRefGoogle Scholar
  16. 16.
    Takahama, Y., Suzuki, H., Katz, K. S., Grusby, M.J., and Singer, A. (1994) Positive selection of CD4+ T cells by TCR ligation without aggregation even in the absence of MHC. Nature (Lond) 371:67–70.CrossRefGoogle Scholar
  17. 17.
    Ashton-Rickardt, P. G. and Tonegawa, S. (1994) A differential-avidity model for T-cell selection. Immunol. Today 15:362–366.PubMedCrossRefGoogle Scholar
  18. 18.
    Sebzda, E., Wallace, V. A., Mayer, J., Yeung, R.S., Mak, T. W., and Ohashi, P. S. (1994) Positive and negative thymocyte selection induced by different concentrations of a single peptide. Science 263:1615–1618.PubMedCrossRefGoogle Scholar
  19. 19.
    Singer, A. (2002) New perspectives on a developmental dilemma: the kinetic signaling model and the importance of signal duration for the CD4/CD8 lineage decision. Curr. Opin. Immunol. 14:207–215.PubMedCrossRefGoogle Scholar
  20. 20.
    Takahama, Y. (2006) Journey through the thymus: stromal guides for T-cell development and selection. Nat. Rev. Immunol. 6:127–135.PubMedCrossRefGoogle Scholar
  21. 21.
    Klein, L. and Kyewski, B. (2000) “Promiscuous” expression of tissue antigens in the thymus: a key to T-cell tolerance and autoimmunity? J. Mol. Med. 78:483–494.CrossRefGoogle Scholar
  22. 22.
    Anderson, M. S., Venanzi, E. S., Klein, L., Chen, Z., Berzins, S. P., Turley, S. J., von Boehmer, H., Bronson, R., Dierich, A., Benoist, C., and Mathis, D. (2002) Projection of an immunological self shadow within the thymus by the aire protein. Science 298:1395–1401.PubMedCrossRefGoogle Scholar
  23. 23.
    Boyd, R. L., Tucek, C. L., Godfrey, D. I., Izon, D. J., Wilson, T. J., Davidson, N. J., Bean, A. G., Ladyman, H. M., Ritter, M. A., and Hugo, P. (1993) The thymic microenvironment. Immunol. Today. 14:445–459.PubMedCrossRefGoogle Scholar
  24. 24.
    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.CrossRefGoogle Scholar
  25. 25.
    Rossi, S. W., Jenkinson, W. E., Anderson, G., and Jenkinson, E. J. (2006) Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature (Lond) 441:988–991.CrossRefGoogle Scholar
  26. 26.
    Bleul, C. C., Corbeaux, T., Reuter, A., Fisch, P., Monting, J. S., and Boehm, T. (2006) Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature (Lond) 441:992–996.CrossRefGoogle Scholar
  27. 27.
    Lindsay, E. A., Vitelli, F., Su, H., Morishima, M., Huynh, T., Pramparo, T., Jurecic, V., Ogunrinu, G., Sutherland, H. F., Scambler, P. J., Bradley, A., and Baldini, A. (2001) Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice. Nature (Lond) 410:97–101.CrossRefGoogle Scholar
  28. 28.
    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.PubMedCrossRefGoogle Scholar
  29. 29.
    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.PubMedGoogle Scholar
  30. 30.
    Nehls, M., Pfeifer, D., Schorpp, M., Hedrich, H., and Boehm, T. (1994) New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature (Lond) 372:103–107.CrossRefGoogle Scholar
  31. 31.
    Anderson, G., Jenkinson, E. J., Moore N. C., and Owen, J. J. T. (1993) MHC class II-positive epithelium and mesenchyme cells are both required for T-cell development in the thymus. Nature (Lond) 362:70–73.CrossRefGoogle Scholar
  32. 32.
    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.PubMedCrossRefGoogle Scholar
  33. 33.
    Shores, E.W., Van Ewijk, W., and Singer, A. (1991) Disorganization and restoration of thymic medullary epithelial cells in T cell receptor-negative scid mice: evidence that receptor-bearing lymphocytes influence maturation of the thymic microenvironment. Eur. J. Immunol. 21:1657–1661.PubMedCrossRefGoogle Scholar
  34. 34.
    Ritter, M. A. and Boyd, R. L. (1993) Development in the thymus: it takes two to tango. Immunol. Today 14:462–469.PubMedCrossRefGoogle Scholar
  35. 35.
    van Ewijk, W., Shores, E. W., and Singer, A. (1994) Crosstalk in the mouse thymus. Immunol. Today 15:214–217.PubMedCrossRefGoogle Scholar
  36. 36.
    Starr, T. K., Jameson, S. C., and Hogquist, K. A. (2003) Positive and negative selection of T cells. Annu. Rev. Immunol. 21:139–176.PubMedCrossRefGoogle Scholar
  37. 37.
    Ignatowicz, L., Kappler, J., and Marrack, P. (1996) The repertoire of T cells shaped by a single MHC/peptide ligand. Cell 84:521–529.PubMedCrossRefGoogle Scholar
  38. 38.
    Huseby, E. S., White, J., Crawford, F., Vass, T., Becker, D., Pinilla, C., Marrack, P., and Kappler, J. W. (2005) How the T cell repertoire becomes peptide and MHC specific. Cell 122:247–260.PubMedCrossRefGoogle Scholar
  39. 39.
    Pawlowski, T., Elliott, J. D., Loh, D. Y., and Staerz, U. D. (1993) Positive selection of T lymphocytes on fibroblasts. Nature (Lond) 364:642–645.CrossRefGoogle Scholar
  40. 40.
    Hugo, P., Kappler, J. W., McCormack, J. E., and Marrack, P. (1993) Fibroblasts can induce thymocyte positive selection in vivo. Proc. Natl. Acad. Sci. U. S. A. 90:10335–10339.PubMedCrossRefGoogle Scholar
  41. 41.
    Yasutomo, K., Lucas, B., and Germain, R. N. (2000) TCR signaling for initiation and completion of thymocyte positive selection has distinct requirements for ligand quality and presenting cell type. J. Immunol. 165:3015–3022.PubMedGoogle Scholar
  42. 42.
    Li, W., Kim, M. G., Gourley, T. S., McCarthy, B.P., Sant'Angelo, D. B., and Chang, C. H. (2005) An alternate pathway for CD4 T cell development: thymocyte-expressed MHC class II selects a distinct T cell population. Immunity 23:375–386.PubMedCrossRefGoogle Scholar
  43. 43.
    Choi, E. Y., Jung, K. C., Park, H. J., Chung, D. H., Song, J. S., Yang, S. D., Simpson, E., and Park, S. H. (2005) Thymocyte—thymocyte interaction for efficient positive selection and maturation of CD4 T cells. Immunity 23:387–396.PubMedCrossRefGoogle Scholar
  44. 44.
    Horai, R., Mueller, K. L., Handon, R. A., Cannons, J. L., Anderson, S. M., Kirby, M. R., and Schwartzberg, P. L. (2007) Requirements for selection of conventional and innate T lymphocyte lineages. Immunity 27:775–785.PubMedCrossRefGoogle Scholar
  45. 45.
    Kirberg, J., Bosco, N., Deloulme, J. C., Ceredig, R., and Agenes, F. (2008) Peripheral T lymphocytes recirculating back into the thymus can mediate thymocyte positive selection. J. Immunol. 181:1207–1214.PubMedGoogle Scholar
  46. 46.
    Murata, S., Sasaki, K., Kishimoto, T., Niwa, S., Hayashi, H., Takahama, Y., and Tanaka, K. (2007) Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 316:1349–1353.PubMedCrossRefGoogle Scholar
  47. 47.
    Rock, K. L. and Goldberg, A. L. (1999) Degradation of cell proteins and the generation of MHC class I-presented peptides. Annu. Rev. Immunol. 17:739–779.PubMedCrossRefGoogle Scholar
  48. 48.
    Kloetzel, P. M. (2001) Antigen processing by the proteasome. Nat. Rev. Mol. Cell. Biol. 2:179–187.PubMedCrossRefGoogle Scholar
  49. 49.
    Coux, O., Tanaka, K., and Goldberg, A. L. (1996) Structure and functions of the 20S and 26S proteasomes. Annu. Rev. Biochem. 65:801–847.PubMedCrossRefGoogle Scholar
  50. 50.
    Baumeister, W., Walz, J., Zühl, F., and Seemüller, E. (1998) The proteasome: paradigm of a self-compartmentalizing protease. Cell 92:367–380.PubMedCrossRefGoogle Scholar
  51. 51.
    Tanaka, K. and Kasahara, M. (1998) The MHC class I ligand-generating system: roles of immunoproteasomes and the interferon-gamma-inducible proteasome activator PA28. Immunol. Rev. 163:161–176.PubMedCrossRefGoogle Scholar
  52. 52.
    Cascio, P., Hilton, C., Kisselev, A. F., Rock, K. L., and Goldberg, A.L. (2001) 26S proteasomes and immunoproteasomes produce mainly N-extended versions of an antigenic peptide. EMBO J. 20:2357–2366.PubMedCrossRefGoogle Scholar
  53. 53.
    Rock, K. L., York, I. A., and Goldberg, A. L. (2004) Post-proteasomal antigen processing for major histocompatibility complex class I presentation. Nat. Immunol. 5:670–677.PubMedCrossRefGoogle Scholar
  54. 54.
    Young, A. C., Nathenson, S. G., and Sacchettini, J. C. (1995) Structural studies of class I major histocompatibility complex proteins: insights into antigen presentation. FASEB J. 9:26–36.PubMedGoogle Scholar
  55. 55.
    Fehling, H. J., Swat, W., Laplace, C., Kühn, R., Rajewsky, K., Müller, U., and von Boehmer, H. (1994) MHC class I expression in mice lacking the proteasome subunit LMP-7. Science 265:1234–1237.PubMedCrossRefGoogle Scholar
  56. 56.
    Murata, S., Takahama, Y., and Tanaka, K. (2008) Thymoproteasome: probable role in generating positively selecting peptides. Curr. Opin. Immunol. 20(2):192–196.PubMedCrossRefGoogle Scholar
  57. 57.
    Takahama, Y., Tanaka, K., and Murata, S. (2008) Modest cortex and promiscuous medulla for thymic repertoire formation. Trends Immunol. 29:251–255.PubMedCrossRefGoogle Scholar
  58. 58.
    Honey, K. and Rudensky, A. Y. (2003) Lysosomal cysteine proteases regulate antigen presentation. Nat. Rev. Immunol. 3:472–482.PubMedCrossRefGoogle Scholar
  59. 59.
    Nakagawa, T., Roth, W., Wong, P., Nelson, A., Farr, A., Deussing, J., Villadangos, J. A., Ploegh, H., Peters, C., and Rudensky, A. Y. (1998) Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. Science 280:450–453.PubMedCrossRefGoogle Scholar
  60. 60.
    Honey, K., Nakagawa, T., Peters, C., and Rudensky, A. (2002) Cathepsin L regulates CD4+ T cell selection independently of its effect on invariant chain: a role in the generation of positively selecting peptide ligands. J. Exp. Med. 195:1349–1358.PubMedCrossRefGoogle Scholar
  61. 61.
    Bousso, P., Bhakta, N. R., Lewis, R. S., and Robey, E. (2002) Dynamics of thymocyte-stromal cell interactions visualized by two-photon microscopy. Science 296:1876–1880.PubMedCrossRefGoogle Scholar
  62. 62.
    Bhakta, N. R., Oh, D. Y., and Lewis, R. S. (2005) Calcium oscillations regulate thymocyte motility during positive selection in the three-dimensional thymic environment. Nat. Immunol. 6:143–151.PubMedCrossRefGoogle Scholar
  63. 63.
    Ngo, V. N., Tang, H. L., and Cyster, J. G. (1998) Epstein-Barr virus-induced molecule 1 ligand chemokine is expressed by dendritic cells in lymphoid tissues and strongly attracts naive T cells and activated B cells. J. Exp. Med. 188:181–191.PubMedCrossRefGoogle Scholar
  64. 64.
    Campbell, J. J., Pan, J., and Butcher, E. C. (1999) Developmental switches in chemokine responses during T cell maturation. J. Immunol. 163:2353–2357.PubMedGoogle Scholar
  65. 65.
    Ueno, T., Saito, F., Gray, D. H., Kuse, S., Hieshima, K., Nakano, H., Kakiuchi, T., Lipp, M., Boyd, R. L., and Takahama, Y. (2004) CCR7 signals are essential for cortex-medulla migration of developing thymocytes. J. Exp. Med. 200:493–505.PubMedCrossRefGoogle Scholar
  66. 66.
    Kurobe, H., Liu, C., Ueno, T., Saito, F., Ohigashi, I., Seach, N., Arakaki, R., Hayashi, Y., Kitagawa, T., Lipp, M., Boyd, R. L., and Takahama, Y. (2006) CCR7-dependent cortex-to-medulla migration of positively selected thymocytes is essential for establishing central tolerance. Immunity 24:165–177.PubMedCrossRefGoogle Scholar
  67. 67.
    Hüpken, U. E., Wengner, A. M., Loddenkemper, C., Stein, H., Heimesaat, M. M., Rehm, A., and Lipp, M. (2007) CCR7 deficiency causes ectopic lymphoid neogenesis and disturbed mucosal tissue integrity. Blood 109:886–895.CrossRefGoogle Scholar
  68. 68.
    Davalos-Misslitz, A. C. M, Rieckenberg, J., Willenzon, S., Worbs, T., Kremmer, E., Bernhardt, G., and Fürster R. (2007) Generalized multi-organ autoimmunity in CCR7-deficient mice. Eur. J. Immunol. 37:613–622.PubMedCrossRefGoogle Scholar
  69. 69.
    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 (Lond) 414:763–768.CrossRefGoogle Scholar
  70. 70.
    Weih, F., Carrasco, D., Durham, S. K., Barton, D. S., Rizzo, C. A., Ryseck, R. P., Lira, S. A., and Bravo, R. (1995) Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kB/Rel family. Cell 80:331–340.PubMedCrossRefGoogle Scholar
  71. 71.
    DeKoning, J., DiMolfetto, L., Reilly, C., Wei, Q., Havran, W., and Lo, D. (1997) Thymic cortical epithelium is sufficient for the development of mature T cells in relB-deficient mice. J. Immunol. 158:2558–2566.PubMedGoogle Scholar
  72. 72.
    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 LTbR. J. Exp. Med. 198:757–769.PubMedCrossRefGoogle Scholar
  73. 73.
    Heath, V. L., Moore, N. C., Parnell, S. M., and Mason, D.W. (1998) Intrathymic expression of genes involved in organ specific autoimmune disease. J. Autoimmun. 11:309–318.PubMedCrossRefGoogle Scholar
  74. 74.
    Klein, L., Klein, T., Rüther, U., and Kyewski, B. (1998) CD4 T cell tolerance to human C-reactive protein, an inducible serum protein, is mediated by medullary thymic epithelium. J. Exp. Med. 188:5–16.PubMedCrossRefGoogle Scholar
  75. 75.
    Sospedra, M., Ferrer-Francesch, X., Domínguez, O., Juan, M., Foz-Sala, M., and Pujol-Borrell, R. (1998) Transcription of a broad range of self-antigens in human thymus suggests a role for central mechanisms in tolerance toward peripheral antigens. J. Immunol. 161:5918–5929.PubMedGoogle Scholar
  76. 76.
    Werdelin, O., Cordes, U., and Jensen, T. (1998) Aberrant expression of tissue-specific proteins in the thymus: a hypothesis for the development of central tolerance. Scand. J. Immunol. 47:95–100.PubMedCrossRefGoogle Scholar
  77. 77.
    Klein, L., Klugmann, M., Nave, K. A., Tuohy, V.K., and Kyewski, B. (2000) Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nat. Med. 6:56–61.PubMedCrossRefGoogle Scholar
  78. 78.
    Derbinski, J., Schulte, A., Kyewski, B., and Klein, L. (2001) Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat. Immunol. 2:1032–1039.PubMedCrossRefGoogle Scholar
  79. 79.
    Heino, M., Peterson, P., Kudoh, J., Nagamine, K., Lagerstedt, A., Ovod, V., Ranki, A., Rantala, I., Nieminen, M., Tuukkanen, J., Scott, H. S., Antonarakis, S. E., Shimizu, N., and Krohn, K. (1999) Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. Biochem. Biophys. Res. Commun. 257:821–825.PubMedCrossRefGoogle Scholar
  80. 80.
    Heino, M., Peterson, P., Sillanpää, N., Guérin, S., Wu, L., Anderson, G., Scott, H. S., Antonarakis, S. E., Kudoh, J., Shimizu, N., Jenkinson, E. J., Naquet, P., and Krohn, K. J. (2000) RNA and protein expression of the murine autoimmune regulator gene (Aire) in normal, RelB-deficient and in NOD mouse. Eur. J. Immunol. 30:1884–1893.PubMedCrossRefGoogle Scholar
  81. 81.
    Zuklys, S., Balciunaite, G., Agarwal, A., Fasler-Kan, E., Palmer, E., and Holländer, G. A. (2000) Normal thymic architecture and negative selection are associated with Aire expression, the gene defective in the autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) J. Immunol. 165:1976–1983.Google Scholar
  82. 82.
    Derbinski, J., Gäbler, J., Brors, B., Tierling, S., Jonnakuty, S., Hergenhahn, M., Peltonen, L., Walter, J., and Kyewski, B. (2005) Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202:33–45.PubMedCrossRefGoogle Scholar
  83. 83.
    Philpott, K. L., Viney, J. L., Kay, G., Rastan, S., Gardiner, E. M., Chae, S., Hayday, A. C., and Owen, M. J. (1992) Lymphoid development in mice congenitally lacking T cell receptor αβ-expressing cells. Science 256:1448–1452.PubMedCrossRefGoogle Scholar
  84. 84.
    Surh, C. D., Ernst, B., and Sprent, J. (1992) Growth of epithelial cells in the thymic medulla is under the control of mature T cells. J. Exp. Med. 176:611–616.PubMedCrossRefGoogle Scholar
  85. 85.
    Negishi, I., Motoyama, N., Nakayama, K., Nakayama, K., Senju, S., Hatakeyama, S., Zhang, Q., Chan, A. C., and Loh, D. Y. (1995) Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature (Lond) 376:435–438.CrossRefGoogle Scholar
  86. 86.
    Nasreen, M., Ueno, T., Saito, F., and Takahama, Y. (2003) In vivo treatment of class II MHC-deficient mice with anti-TCR antibody restores the generation of circulating CD4 T cells and optimal architecture of thymic medulla. J. Immunol. 171:3394–3400.PubMedGoogle Scholar
  87. 87.
    Hikosaka, Y., Nitta, T., Ohigashi, I., Yano, K., Ishimaru, N., Hayashi, Y., Matsumoto, M., Matsuo, K., Penninger, J. M., Takayanagi, H., Yokota, Y., Yamada, H., Yoshikai, Y., Inoue, J., Akiyama, T., and Takahama, Y. (2008) The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 29(3):438–450.PubMedCrossRefGoogle Scholar
  88. 88.
    Rossi, S. W., Kim, M. Y., Leibbrandt, A., Parnell, S. M., Jenkinson, W. E., Glanville, S.H., McConnell, F. M., Scott, H. S., Penninger, J. M., Jenkinson, E. J., Lane, P. J., and Anderson, G. (2007) RANK signals from CD4+3- inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J. Exp. Med. 204:1267–1272.PubMedCrossRefGoogle Scholar
  89. 89.
    Anderson, G., Lane, P. J., and Jenkinson, E. J. (2007) Generating intrathymic microenvironments to establish T-cell tolerance. Nat. Rev. Immunol. 7:954–963.PubMedCrossRefGoogle Scholar
  90. 90.
    White, A. J., Withers, D. R., Parnell, S. M., Scott, H. S., Finke, D., Lane, P. J., Jenkinson, E. J., and Anderson, G. (2008) Sequential phases in the development of Aire-expressing medullary thymic epithelial cells involve distinct cellular input. Eur. J. Immunol. 38:942–947.PubMedCrossRefGoogle Scholar
  91. 91.
    Fuleihan, R., Ahern, D., and Geha, R. S. (1995) CD40 ligand expression is developmentally regulated in human thymocytes. Clin. Immunol. Immunopathol. 76:52–58.PubMedCrossRefGoogle Scholar
  92. 92.
    Dunn, R. J., Luedecker, C. J., Haugen, H. S., Clegg, C. H., and Farr, A. G. (1997) Thymic overexpression of CD40 ligand disrupts normal thymic epithelial organization. J. Histochem. Cytochem. 45:129–141.PubMedGoogle Scholar
  93. 93.
    Clegg, C. H., Rulffes, J. T., Haugen, H. S., Hoggatt, I. H., Aruffo, A., Durham, S. K., Farr, A. G., and Hollenbaugh, D. (1997) Thymus dysfunction and chronic inflammatory disease in gp39 transgenic mice. Int. Immunol. 9:1111–1122.PubMedCrossRefGoogle Scholar
  94. 94.
    Akiyama, T., Shimo, Y., Yanai, H., Qin, K., Ohshima, D., Maruyama, Y., Asaumi, Y., Kitazawa, J., Takayanagi, T., Penninger, J. M., Matsumoto, M., Nitta, T., Takahama, Y., and Inoue, J. (2008) The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29:423–437.PubMedCrossRefGoogle Scholar
  95. 95.
    Hassall, A. H. (1849) The Microscopic Anatomy of the Human Body, in Health and Disease. Highley, London.Google Scholar
  96. 96.
    Symington, J. (1898) The thymus gland in the marsupialia. J. Anat. Physiol. 32(Pt 2):278–291.PubMedGoogle Scholar
  97. 97.
    Lewis, T. (1904) Observations upon the distribution and structure of haemolymph glands in mammalia and aves, including a preliminary note on the thymus. J. Anat. Physiol. 38(Pt 3):312–324.PubMedGoogle Scholar
  98. 98.
    Goodall, A. (1905) The post-natal changes in the thymus of guinea-pigs, and the effect of castration on thymus structure. J. Physiol. 32:191–198.PubMedGoogle Scholar
  99. 99.
    van den Brink, M. R., Alpdogan, O., Boyd, R. L. (2004) Strategies to enhance T-cell recon-stitution in immunocompromised patients. Nat. Rev. Immunol. 4:856–867.PubMedCrossRefGoogle Scholar
  100. 100.
    Gray, D. H., Ueno, T., Chidgey, A. P., Malin, M., Goldberg, G. L., Takahama, Y., and Boyd, R. L. (2005) Controlling the thymic microenvironment. Curr. Opin. Immunol. 17:137–143.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Takeshi Nitta
    • 1
  • Yousuke Takahama
    • 1
  1. 1.Division of Experimental Immunology, Institute for Genome ResearchUniversity of TokushimaTokushimaJapan

Personalised recommendations