Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Journey through the thymus: stromal guides for T-cell development and selection

Key Points

  • The seeding of the thymus is mediated by at least two different pathways: the vasculature-independent embryonic pathway, in which the role of chemokines, such as CC-chemokine ligand 21 (CCL21) and CCL25, has been implicated, and the vasculature-dependent postnatal pathway, in which the adhesive interaction between platelet (P)-selectin and P-selectin glycoprotein ligand 1 is involved.

  • In the postnatal thymus, double-negative (DN) thymocytes relocate outwards from the cortico–medullary junction to the subcapsular region of the thymic cortex. The role of several chemokine receptors, including CXC-chemokine receptor 4 (CXCR4), CC-chemokine receptor 7 (CCR7) and CCR9, has been described.

  • Positively selected DP thymocytes relocate from the cortex to the medulla. Chemotaxis through CCR7 expressed by T-cell-receptor-stimulated thymocytes and CCR7 ligands expressed by medullary thymic epithelial cells is involved in this cortex-to-medulla migration.

  • The medulla is implicated in the establishment of tolerance to tissue-specific antigens and the generation of regulatory T cells.

  • Chemotaxis through sphingosine-1-phosphate (S1P) receptor 1 expressed by mature single-positive thymocytes and circulating S1P seems to be involved in thymocyte export from the adult thymus.

  • The generation of multiple microenvironments in the thymus, such as the cortex and the medulla, requires crosstalk signals from developing thymocytes.

Abstract

Lympho–stromal interactions in multiple microenvironments within the thymus have a crucial role in the regulation of T-cell development and selection. Recent studies have implicated that chemokines that are produced by thymic stromal cells have a pivotal role in positioning developing T cells within the thymus. In this Review, I discuss the importance of stroma-derived chemokines in guiding the traffic of developing thymocytes, with an emphasis on the processes of cortex-to-medulla migration and T-cell-repertoire selection, including central tolerance.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The thymus architecture.
Figure 2: Traffic of thymocytes for T-cell development and selection.
Figure 3: Crosstalk between thymocytes and thymic stromal cells.
Figure 4: Positive selection and migration to the medulla.

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Bevan, M. J. In a radiation chimaera, host H-2 antigens determine the immune responsiveness of donor cytotoxic cells. Nature 269, 417–418 (1977).

    Article  CAS  PubMed  Google Scholar 

  3. Zinkernagel, R. M. et al. On the thymus in the differentiation of “H-2 self-recognition” by T cells: evidence for dual recognition? J. Exp. Med. 147, 882–896 (1978).

    Article  CAS  PubMed  Google Scholar 

  4. Sainte-Marie, G. & Leblond, C. P. Cytologic features and cellular migration in the cortex and medulla of thymus in the young adult rat. Blood 23, 275–299 (1964).

    Article  CAS  PubMed  Google Scholar 

  5. Cantor, H. & Weissman, I. Development and function of subpopulations of thymocytes and T lymphocytes. Prog. Allergy 20, 1–64 (1976).

    CAS  PubMed  Google Scholar 

  6. Stutman, O. Intrathymic and extrathymic T cell maturation. Immunol. Rev. 42, 138–184 (1978).

    Article  CAS  PubMed  Google Scholar 

  7. Bhan, A. K., Reinherz, E. L., Poppema, S., McCluskey, R. T. & Schlossman, S. F. Location of T cell and major histocompatibility complex antigens in the human thymus. J. Exp. Med. 152, 771–782 (1980).

    Article  CAS  PubMed  Google Scholar 

  8. 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 

  9. Gray, D. H. D. et al. Controlling the thymic microenvironment. Curr. Opin. Immunol. 17, 137–143 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Scollay, R. G., Butcher, E. C. & Weissman, I. L. Thymus cell migration. Quantitative aspects of cellular traffic from the thymus to the periphery in mice. Eur. J. Immunol. 10, 210–218 (1980).

    Article  CAS  PubMed  Google Scholar 

  11. Egerton, M., Scollay, R. & Shortman, K. Kinetics of mature T-cell development in the thymus. Proc. Natl Acad. Sci. USA 87, 2579–2582 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Goldrath, A. W. & Bevan, M. J. Selecting and maintaining a diverse T-cell repertoire. Nature 402, 255–262 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Shores, E. W., van Ewijk, W. & Singer, A. 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 (1991).

    Article  CAS  PubMed  Google Scholar 

  14. van Ewijk, W., Shores, E. W. & Singer, A. Crosstalk in the mouse thymus. Immunol. Today 15, 214–217 (1994). References 13 and 14 were the first to show that thymocyte development affects the development of TECs, coining the idea of crosstalk in the thymus.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Haynes, B. F. & Heinly, C. S. Early human T cell development: analysis of the human thymus at the time of initial entry of hematopoietic stem cells into the fetal thymic microenvironment. J. Exp. Med. 181, 1445–1458 (1995).

    Article  CAS  PubMed  Google Scholar 

  19. Bleul, C. C. & Boehm, T. Chemokines define distinct microenvironments in the developing thymus. Eur. J. Immunol. 30, 3371–3379 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Liu, C. et al. The role of CCL21 in recruitment of T precursor cells to fetal thymus. Blood 105, 31–39 (2005). References 19 and 20 show the expression of chemokines in the fetal thymus. Reference 20 further examines the role of chemokines in fetal thymus colonization using a time-lapse visualization technique.

    Article  CAS  PubMed  Google Scholar 

  21. Wurbel, M. A. et al. Mice lacking the CCR9 CC-chemokine receptor show a mild impairment of early T- and B-cell development and a reduction in T-cell receptor γδ+ gut intraepithelial lymphocytes. Blood 98, 2626–2632 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Ara, T. et al. A role of CXC chemokine ligand 12/stromal cell-derived factor-1/pre-B cell growth stimulating factor and its receptor CXCR4 in fetal and adult T cell development in vivo. J. Immunol. 170, 4649–4655 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. 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 shows that the adult thymus is seeded at the cortico–medullary junction and that immature thymocytes migrate outwards to the subcapsular zone.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rossi, F. M. V. et al. Recruitment of adult thymic progenitors is regulated by P-selectin and its ligand PSGL-1. Nature Immunol. 6, 626–634 (2005). This study provides the molecular mechanism of adult thymus seeding by showing the involvement of P-selectin and PSGL1.

    Article  CAS  Google Scholar 

  25. Fossa, D. L., Donskoya, E. & Goldschneider, I. The importation of hematogenous precursors by the thymus is a gated phenomenon in normal adult mice. J. Exp. Med. 193, 365–374 (2001).

    Article  Google Scholar 

  26. 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).

    Article  CAS  PubMed  Google Scholar 

  27. Havran, W. L. & Allison, J. P. Developmentally ordered appearance of thymocytes expressing different T-cell antigen receptors. Nature 335, 443–445 (1988).

    Article  CAS  PubMed  Google Scholar 

  28. Coltey, M. et al. Analysis of the first two waves of thymus homing stem cells and their T cell progeny in chick–quail chimeras. J. Exp. Med. 170, 543–557 (1989).

    Article  CAS  PubMed  Google Scholar 

  29. Dunon, D. et al. Ontogeny of the immune system: γδ and αβ T cells migrate from thymus to the periphery in alternating waves. J. Exp. Med. 186, 977–988 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ikuta, K. et al. A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells. Cell 62, 863–874 (1990).

    Article  CAS  PubMed  Google Scholar 

  31. Weber-Arden, J., Wilbert, O. M., Kabelitz, D. & Arden, B. Vδ repertoire during thymic ontogeny suggests three novel waves of γδ TCR expression. J. Immunol. 164, 1002–1012 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Pearse, M. et al. A murine early thymocyte developmental sequence is marked by transient expression of the interleukin 2 receptor. Proc. Natl Acad. Sci. USA 86, 1614–1618 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Shinkai, Y. et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68, 855–867 (1992).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Zúñiga-Pflücker, J. C. T-cell development made simple. Nature Rev. Immunol. 4, 67–72 (2004).

    Article  CAS  Google Scholar 

  36. Peschon, J. J. et al. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J. Exp. Med. 180, 1955–1960 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. von Freedem-Jeffry, U. et al. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J. Exp. Med. 181, 1519–1526 (1995).

    Article  Google Scholar 

  38. 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 

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

    Article  CAS  PubMed  Google Scholar 

  40. 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 

  41. Misslitz, A. et al. Thymic T cell development and progenitor localization depend on CCR7. J. Exp. Med. 200, 481–491 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Benz, C., Heinzel, K. & Bleul, C. C. Homing of immature thymocytes to the subcapsular microenvironment within the thymus is not an absolute requirement for T cell development. Eur. J. Immunol. 34, 3652–3663 (2004). References 40–42 show the involvement of chemokines in the outward migration of DN thymocytes to the subcapsular zone.

    Article  CAS  PubMed  Google Scholar 

  43. Raulet, D. H., Garman, R. D., Saito, H. & Tonegawa, S. Developmental regulation of T-cell receptor gene expression. Nature 314, 103–107 (1985).

    Article  CAS  PubMed  Google Scholar 

  44. von Boehmer, H. & Fehling, H. J. Structure and function of the pre-T cell receptor. Annu. Rev. Immunol. 15, 433–452 (1997).

    Article  CAS  PubMed  Google Scholar 

  45. Irving, B. A., Alt, F. W. & Killeen, N. Thymocyte development in the absence of pre-T cell receptor extracellular immunoglobulin domains. Science 280, 905–908 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Ciofani, M. & Zúñiga-Pflücker, J. C. Notch promotes survival of pre-T cells at the β-selection checkpoint by regulating cellular metabolism. Nature Immunol. 6, 881–888 (2005).

    Article  CAS  Google Scholar 

  47. Takahama, Y., Letterio, J. J., Suzuki, H., Farr, A. G. & Singer, A. Early progression of thymocytes along the CD4/CD8 developmental pathway is regulated by a subset of thymic epithelial cells expressing transforming growth factor β. J. Exp. Med. 179, 1495–1506 (1994).

    Article  CAS  PubMed  Google Scholar 

  48. Kisielow, P., Teh, H. S., Bluthmann, H. & von Boehmer, H. Positive selection of antigen-specific T cells in thymus by restricting MHC molecules. Nature 335, 730–733 (1988).

    Article  CAS  PubMed  Google Scholar 

  49. Jameson, S. C., Hogquist, K. A. & Bevan, M. J. Positive selection of thymocytes. Annu. Rev. Immunol. 13, 93–126 (1995).

    Article  CAS  PubMed  Google Scholar 

  50. Witt, C. M., Raychaudhuri, S., Schaefer, B., Chakraborty, A. K. & Robey, E. A. Directed migration of positively selected thymocytes visualized in real time. PLoS Biol. 3, e160 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Bousso, P., Bhakta, N. R., Lewis, R. S. & Robey, E. Dynamics of thymocyte-stromal cell interactions visualized by two-photon microscopy. Science 296, 1876–1880 (2002). Through devising in situ visualization of the thymus microenvironment with two-photon microscopy, references 50 and 51 describe the behaviour and motility of developing thymocytes.

    Article  CAS  PubMed  Google Scholar 

  52. Kim, C. H., Pelus, L. M., White, J. R. & Broxmeyer, H. E. Differential chemotactic behavior of developing T cells in response to thymic chemokines. Blood 91, 4434–4443 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  54. Ueno, T. et al. CCR7 signals are essential for cortex-to-medulla migration of developing thymocytes. J. Exp. Med. 200, 493–505 (2004). This study shows the involvement of CCR7 and its ligands in the cortex-to-medulla migration of positively selected thymocytes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kwan, J. & Killeen, N. CCR7 directs the migration of thymocytes into the thymic medulla. J. Immunol. 172, 3999–4007 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Eggli, P., Schaffner, T., Gerber, H. A., Hess, M. W. & Cottier, H. Accessibility of thymic cortical lymphocytes to particles translocated from the peritoneal cavity to parathymic lymph nodes. Thymus 8, 129–139 1986).

    CAS  PubMed  Google Scholar 

  57. Nieuwenhuis, P. et al. The transcapsular route: a new way for (self-) antigens to by-pass the blood–thymus barrier. Immunol. Today 9, 372–375 (1988).

    Article  CAS  PubMed  Google Scholar 

  58. Shores, E. W., van Ewijk, W. & Singer, A. Maturation of medullary thymic epithelium requires thymocytes expressing fully assembled CD3–TCR complexes. Int. Immunol. 6, 1393–1402 (1994).

    Article  CAS  PubMed  Google Scholar 

  59. Nasreen, M., Ueno, T., Saito, F. & Takahama, Y. 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 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Burkly, L. et al. Expression of relB is required for the development of thymic medulla and dendritic cells. Nature 373, 531–536 (1995).

    Article  CAS  PubMed  Google Scholar 

  61. 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 

  62. Kajiura, F. et al. NF-κB-inducing kinase establishes self-tolerance in a thymic-stroma dependent manner. J. Immunol. 172, 2067–2075 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Akiyama, T. et al. Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 308, 248–251 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Reichert, R. A., Weissman, I. L. & Butcher, E. C. Phenotypic analysis of thymocytes that express homing receptors for peripheral lymph nodes. J. Immunol. 136, 3521–3528 (1986).

    CAS  PubMed  Google Scholar 

  65. Bendelac, A., Matzinger, P., Seder, R. A., Paul, W. E. & Schwartz, R. H. Activation events during thymic selection. J. Exp. Med. 175, 731–742 (1992).

    Article  CAS  PubMed  Google Scholar 

  66. Ramsdell, F., Jenkins, M., Dinh, Q. & Fowlkes, B. J. The majority of CD4+8 thymocytes are functionally immature. J. Immunol. 147, 1779–1785 (1991).

    CAS  PubMed  Google Scholar 

  67. Kyewski, B. & Derbinski, J. Self-representation in the thymus: an extended view. Nature Rev. Immunol. 4, 688–698 (2004).

    Article  CAS  Google Scholar 

  68. Zuklys, S. et al. 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 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Derbinski, J. et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202, 33–45 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Nagamine, K. et al. Positional cloning of the APECED gene. Nature Genet. 17, 393–398 (1997).

    Article  CAS  PubMed  Google Scholar 

  71. Aaltonen, J. et al. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nature Genet. 17, 399–403 (1997).

    Article  Google Scholar 

  72. 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 

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

    Article  CAS  Google Scholar 

  74. Kuroda, N. et al. Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice. J. Immunol. 174, 1862–1870 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Gallegos, A. M. & Bevan, M. J. Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J. Exp. Med. 200, 1039–1049 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Anderson, M. S. et al. The cellular mechanism of Aire control of T cell tolerance. Immunity 23, 227–239 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Sakaguchi, S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Ann. Rev. Immunol. 22, 531–562 (2004).

    Article  CAS  Google Scholar 

  78. Fontenot, J. D. et al. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22, 329–341 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Watanabe, N. et al. Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 436, 1181–1185 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Lieberam, I. & Forster, I. The murine β-chemokine TARC is expressed by subsets of dendritic cells and attracts primed CD4+ T cells. Eur. J. Immunol. 29, 2684–2694 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Alferink, J. et al. Compartmentalized production of CCL17 in vivo: strong inducibility in peripheral dendritic cells contrasts selective absence from the spleen. J. Exp. Med. 197, 585–599 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chantry, D. et al. Macrophage-derived chemokine is localized to thymic medullary epithelial cells and is a chemoattractant for CD3+, CD4+, CD8low thymocytes. Blood 94, 1890–1898 (1999).

    Article  CAS  PubMed  Google Scholar 

  83. Annunziato, F. et al. Macrophage-derived chemokine and EBI1-ligand chemokine attract human thymocytes in different stage of development and are produced by distinct subsets of medullary epithelial cells: possible implications for negative selection. J. Immunol. 165, 238–246 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Chaffin, K. E. & Perlmutter, R. M. A pertussis toxin-sensitive process controls thymocyte emigration. Eur. J. Immunol. 21, 2565–2573 (1991).

    Article  CAS  PubMed  Google Scholar 

  85. Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004). This study shows the role of S1P and its receptor in thymic export.

    Article  CAS  PubMed  Google Scholar 

  86. Allende, M. L., Dreier, J. L., Mandala, S. & Proia, R. L. Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J. Biol. Chem. 279, 15396–15401 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Edsall, L. C. & Spiegel, S. Enzymatic measurement of sphingosine 1-phosphate. Anal. Biochem. 272, 80–86 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Ueno, T. et al. Role for CCR7 ligands in the emigration of newly generated T lymphocytes from the neonatal thymus. Immunity 16, 205–218 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Poznansky, M. C. et al. Thymocyte emigration is mediated by active movement away from stroma-derived factors. J. Clin. Invest. 109, 1101–1110 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kato, S. Thymic microvascular system. Microscopy Res. Tech. 38, 287–299 (1997).

    Article  CAS  Google Scholar 

  91. Ushiki, T. A scanning electron-microscopic study of the rat thymus with special reference to cell types and migration of lymphocytes into the general circulation. Cell Tissue Res. 244, 285–298 (1986).

    Article  CAS  PubMed  Google Scholar 

  92. Michie, S. A. & Rouse, R. V. Traffic of mature lymphocytes into the mouse thymus. Thymus 13, 141–148 (1989).

    CAS  PubMed  Google Scholar 

  93. Prockop, S. E. et al. Stromal cells provide the matrix for migration of early lymphoid progenitors through the thymic cortex. J. Immunol. 169, 4354–4361 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Muller, K. M., Luedecker, C. J., Udey, M. C. & Farr, A. G. Involvement of E-cadherin in thymus organogenesis and thymocyte maturation. Immunity 6, 257–264 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Vergara-Silva, A., Schaefer, K. L. & Berg, L. J. Compartmentalized Eph receptor and ephrin expression in the thymus. Mech. Dev. 119 (Suppl. 1), S225–S229 (2002).

    Article  PubMed  Google Scholar 

  96. Yanagawa, Y., Iwabuchi, K. & Onoe, K. Enhancement of stromal cell-derived factor-1α-induced chemotaxis for CD4/8 double-positive thymocytes by fibronectin and laminin in mice. Immunology 104, 43–49 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  98. Gill, J. et al. Thymic generation and regeneration. Immunol. Rev. 195, 28–50 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Barry, T. S., Jones, D. M., Richter, C. B. & Haynes, B. F. Successful engraftment of human postnatal thymus in severe combined immune deficient (SCID) mice: differential engraftment of thymic components with irradiation versus anti-asialo GM-1 immunosuppressive regimens. J. Exp. Med. 173, 167–180 (1991).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  101. Bhandoola, A. & Sambandam, A. From stem cell to T cell: one route or many? Nature Rev. Immunol. 6, 117–126 (2006).

    Article  CAS  Google Scholar 

  102. Kawamoto, H., Ohmura, K. & Katsura, Y. Presence of progenitors restricted to T, B, or myeloid lineage, but absence of multipotent stem cells, in the murine fetal thymus. J. Immunol. 161, 3799–3802 (1998).

    CAS  PubMed  Google Scholar 

  103. Rodewald, H. R., Kretzschmar, K., Takeda, S., Hohl, C. & Dessing, M. Identification of pro-thymocytes in murine fetal blood: T lineage commitment can precede thymus colonization. EMBO J. 13, 4229–4240 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Harman, B. C. et al. T/B lineage choice occurs prior to intrathymic Notch signaling. Blood 106, 886–892 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Porritt, H. E. et al. Heterogeneity among DN1 prothymocytes reveals multiple progenitors with different capacities to generate T cell and non-T cell lineages. Immunity 20, 735–745 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Sambandam, A. et al. Notch signaling controls the generation and differentiation of early T lineage progenitors. Nature Immunol. 6, 663–670 (2005).

    Article  CAS  Google Scholar 

  107. Benz, C. & Bleul, C. C. A multipotent precursor in the thymus maps to the branching point of the T versus B lineage decision. J. Exp. Med. 202, 21–31 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Taylor, J. R. et al. Expression and function of chemokine receptors on human thymocytes: implications for infection by human immunodeficiency virus type 1. J. Virol. 75, 8752–8760 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wurbel, M. A. et al. The chemokine TECK is expressed by thymic and intestinal epithelial cells and attracts double- and single-positive thymocytes expressing the TECK receptor CCR9. Eur. J. Immunol. 30, 262–271 (2000).

    Article  CAS  PubMed  Google Scholar 

  110. Carramolino, L. et al. Expression of CCR9 β-chemokine receptor is modulated in thymocyte differentiation and is selectively maintained in CD8+ T cells from secondary lymphoid organs. Blood 97, 850–857 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Norment, A. M., Bogatzki, L. Y., Gantner, B. N. & Bevan, M. J. Murine CCR9, a chemokine receptor for thymus-expressed chemokine that is up-regulated following pre-TCR signaling. J. Immunol. 164, 639–648 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Uehara, S., Song, K., Farber, J. M. & Love, P. E. Characterization of CCR9 expression and CCL25/thymus-expressed chemokine responsiveness during T cell development: CD3highCD69+ thymocytes and γδ TCR+ thymocytes preferentially respond to CCL25. J. Immunol. 168, 134–142 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Youn, B. S., Kim, C. H., Smith, F. O. & Broxmeyer, H. E. TECK, an efficacious chemoattractant for human thymocytes, uses GPR-9–6/CCR9 as a specific receptor. Blood 94, 2533–2536 (1999).

    Article  CAS  PubMed  Google Scholar 

  114. Zaitseva, M. et al. Stromal-derived factor 1 expression in the human thymus. J. Immunol. 168, 2609–2617 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I would like to thank current and previous members of the laboratory, especially T. Ueno and C. Liu, for their discussion and experiments on thymocyte traffic and thymic micro environments. I also would like to thank M. Kubo and F. Saito for excellent and skillful assistance in the study. Continuous discussions with many colleagues, including G. Hollander, R. Boyd, H. Petrie, G. Anderson, W. van Ewijk, H. Kawamoto, T. Ushiki and A. Singer, have made essential contributions to the framework of the idea reviewed here. Financial support by the MEXT Grant-in-Aid for scientific research and the JSPS Core-to-Core Program is acknowledged.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Yousuke Takahama's laboratory

Glossary

Thymic primordium

The primordium refers to an organ or tissue in its earliest recognizable stage of development. The primordium of the thymus is generated at the ventral aspect of the third pharyngeal pouch as early as embryonic day 10.5 in mice.

Thymic parenchyma

The parenchyma refers to the functional part of an organ. The parenchyma of the thymus is surrounded by the capsule, the trabeculae and the perivascular spaces.

Two-photon laser fluorescence microscopy

A fluorescence-imaging technique that takes advantage of the fact that fluorescent molecules can absorb two photons simultaneously during excitation before they emit light. This technique greatly reduces photodamage of living specimens, improves tissue penetration depth, allows the distinct separation between excitation and emission wavelengths, and confines the excitation to a discrete focal point.

Interstitial fluid

The fluid in the spaces between cells and tissues, outside the lymphatic or cardiovascular systems. Its composition is similar to plasma and lymph.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

(APECED or autoimmune polyendocrine syndrome type 1). APECED is characterized by the presence of two of three clinical symptoms: Addison's disease and/or hypoparathyroidism and/or chronic mucocutaneous candidiasis. It is caused by a mutation in the gene autoimmune regulator (AIRE).

Hassall's corpuscles

Small clusters or concentric whorls of stratified keratinizing epithelium in the thymic medulla, possibly involved in the negative selection of thymocytes, the generation of regulatory T cells and/or undergoing apoptosis themselves. They are found clearly in the human thymus, but are unclear in the mouse thymus.

G-protein-coupled receptor

(GPCR). A receptor that is composed of seven membrane-spanning helical segments. These receptors associate with G-proteins, which are a family of trimeric intracellular-signalling proteins with common β- and γ-chains, and one of several α-chains. The α-chain determines the nature of the signal that is transmitted from a ligand-occupied GPCR to downstream effector systems.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takahama, Y. Journey through the thymus: stromal guides for T-cell development and selection. Nat Rev Immunol 6, 127–135 (2006). https://doi.org/10.1038/nri1781

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1781

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing