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:

Development of αβ T cells in the human thymus

Nature Reviews Immunology volume 2, pages 760–772 (2002)Cite this article

Key Points

  • The haematopoietic progenitors that enter the thymus are mostly not committed to the T-cell lineage. These cells can develop not only into T cells, but also into natural killer (NK) cells, and lymphoid and myeloid dendritic cells.

  • The cell-fate choice of thymic precursor cells is driven by transcription factors. E proteins and their antagonists, ID proteins, determine whether precursor cells become T cells or NK cells. NOTCH1 is important for T-cell development.

  • T-cell development proceeds through various transitional stages that can be discriminated on the basis of their expression of cell-surface and cytoplasmic proteins and their developmental capacities.

  • Interleukin-7 has an essential role in human T-cell development. It is important for the survival of early T-cell progenitors, but might also control the differentiation of αβ T cells in the human thymus.

  • The selection of early T-cell receptor (TCR)αβ-lineage cells (β-selection) begins with CD4+CD8− pre-T cells and continues as the cells upregulate expression of CD8α and CD8β.

  • Positive selection of CD1A+CD4+CD8+CD45RO+ cells that have a functional TCRαβ dimer is induced by interactions with self-peptide–MHC complexes. It results in the upregulation of expression of the early activation antigen CD69, an increase in expression of the TCR and induction of expression of CD27. Before emigrating from the thymus, the T cells lose expression of CD45RO and acquire CD45RA.

  • TCR excision circles (TRECs) can be used as a marker for recent thymic emigrants, but the TREC content of peripheral T cells is not determined by thymic function only. So, analysis of the TREC content of peripheral T cells should be interpreted with caution.

  • Thymic function declines with age, a process that is known as thymic involution. However, the thymus can still function in adults even at an advanced age. This occurs in clinical settings that are associated with T-cell depletion, such as bone-marrow transplantation and HIV-1 infection.

  • HIV-1 infection markedly affects thymic function. Highly active anti-retroviral therapy (HAART) can restore thymopoiesis in patients with high pre-treatment thymic activity.

Abstract

The thymus is the main producer of αβ T cells and is, therefore, crucial for a normal immune system. The intrathymic developmental pathway of human αβ T cells has now been delineated. The production of new T cells by the thymus decreases with age, and the thymus was thought to be redundant in adults once the peripheral T-cell pool has been formed early in life. However, recent work has shown that the thymus can function even at an advanced age. Research into the production of T cells in clinical settings that are associated with loss of T cells in the periphery has sparked renewed interest in the function of the human thymus.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: A model of the early stages of T-cell development in the thymus.
Figure 2: A model of the transitional stages that are associated with β-selection.

Similar content being viewed by others

References

  1. Markert, M. L. et al. Transplantation of thymus tissue in complete DiGeorge syndrome. N. Engl. J. Med. 341, 1180–1189 (1999).This paper shows that the transplantation of thymi of young children into patients suffering from complete DiGeorge syndrome results in the appearance of mature T cells. This not only describes a much-needed therapeutic intervention for these patients, but also conclusively shows the essential role of the thymus for T-cell development in humans.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Heemskerk, M. H. et al. Inhibition of T-cell and promotion of natural-killer-cell development by the dominant-negative helix-loop-helix factor Id3. J. Exp. Med. 186, 1597–1602 (1997).This is the first paper to show in vitro genetic manipulation of human T-cell development. It shows that overexpression of ID3 in thymic precursors inhibits T-cell development, but stimulates NK-cell development. The data in this paper and those presented in reference 26 indicate that the balance between E- and ID-protein activities determines T-cell versus NK-cell fate.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Verhasselt, B. S. M., Verhelst, D. R., Naessens, E. & Plum, J. Retrovirally transduced CD34++ human cord-blood cells generate T cells expressing high levels of the retroviral encoded green fluorescent protein marker in vitro. Blood 91, 431–440 (1998).

    CAS  PubMed  Google Scholar 

  5. Fischer, A. et al. Naturally occurring primary deficiencies of the immune system. Annu. Rev. Immunol. 15, 93–124 (1997).An excellent review that includes discussions about the effects of gene deficiencies on T-cell development in humans.

    Article  CAS  PubMed  Google Scholar 

  6. Donskoy, E. & Goldschneider, I. Thymocytopoiesis is maintained by blood-borne precursors throughout postnatal life. A study in parabiotic mice. J. Immunol. 148, 1604–1612 (1992).

    CAS  PubMed  Google Scholar 

  7. Blom, B., Res, P., Noteboom, E., Weijer, K. & Spits, H. Prethymic CD34+ progenitors capable of developing into T cells are not committed to the T-cell lineage. J. Immunol. 158, 3571–3577 (1997).

    CAS  PubMed  Google Scholar 

  8. Sánchez, M.-J., Muench, M. O., Roncarolo, M. G., Lanier, L. & Phillips, J. H. Identification of a common T/NK-cell progenitor in human fetal thymus. J. Exp. Med. 180, 569–576 (1994).The first study to prove that T cells and NK cells are derived from a common precursor.

    Article  PubMed  Google Scholar 

  9. Res, P. et al. CD34+CD38dim cells in the human thymus can differentiate into T, natural killer and dendritic cells, but are distinct from pluripotent stem cells. Blood 87, 5196–5206 (1996).

    CAS  PubMed  Google Scholar 

  10. Márquez, C. et al. Identification of a common developmental pathway for thymic natural killer cells and dendritic cells. Blood 91, 2760–2771 (1998).

    PubMed  Google Scholar 

  11. de Yebenes, V. G., Carrasco, Y. R., Ramiro, A. R. & Toribio, M. L. Identification of a myeloid intrathymic pathway of dendritic-cell development marked by expression of the granulocyte–macrophage colony-stimulating factor receptor. Blood 99, 2948–2956 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Spits, H., Couwenberg, F., Bakker, A. Q., Weijer, K. & Uittenbogaart, C. H. Id2 and Id3 inhibit development of CD34+ stem cells into pre-dendritic cell (pre-DC)2 but not into pre-DC1. Evidence for a lymphoid origin of pre-DC2. J. Exp. Med. 192, 1775–1784 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Weijer, K. et al. Intrathymic and extrathymic development of human plasmacytoid dendritic cell precursors in vivo. Blood 99, 2752–2759 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. 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 

  15. Ikawa, T., Kawamoto, H., Fujimoto, S. & Katsura, Y. Commitment of common T/natural killer (NK) progenitors to unipotent T and NK progenitors in the murine fetal thymus revealed by a single progenitor assay. J. Exp. Med. 190, 1617–1626 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Michie, A. M. et al. Clonal characterization of a bipotent T-cell and NK-cell progenitor in the mouse fetal thymus. J. Immunol. 164, 1730–1733 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. 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).Using the mouse thymus as a model, the authors visualized where thymic immigrant precursor cells enter the thymus and how they migrate across the thymus during differentiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kurtzberg, J., Denning, S. M., Nycum, L. M., Singer, K. H. & Haynes, B. F. Immature human thymocytes can be driven to differentiate into nonlymphoid lineages by cytokines from thymic epithelial cells. Proc. Natl Acad. Sci. USA 86, 7575–7579 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Galy, A., Verma, S., Barcena, A. & Spits, H. Precursors of CD3+CD4+CD8+ cells in the human thymus are defined by expression of CD34. Delineation of early events in human thymic development. J. Exp. Med. 178, 391–401 (1993).

    Article  CAS  PubMed  Google Scholar 

  20. Spits, H. et al. Early stages in the development of human T, natural killer and thymic dendritic cells. Immunol. Rev. 165, 75–86 (1998).Different markers are used to distinguish between early cellular stages of human and mouse T-cell development. This overview contains a detailed comparison of the early stages of human and mouse T-cell development on the basis of their developmental capacities and presence of TCR gene rearrangements.

    Article  CAS  PubMed  Google Scholar 

  21. Blom, B. et al. TCR gene rearrangements and expression of the pre-T-cell receptor complex during human T-cell differentiation. Blood 93, 3033–3043 (1999).

    CAS  PubMed  Google Scholar 

  22. Kuo, C. T. & Leiden, J. M. Transcriptional regulation of T-lymphocyte development and function. Annu. Rev. Immunol. 17, 149–187 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Di Santo, J. P., Radtke, F. & Rodewald, H. R. To be or not to be a pro-T? Curr. Opin. Immunol. 12, 159–165 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Engel, I. & Murre, C. The function of E- and Id proteins in lymphocyte development. Nature Rev. Immunol. 1, 193–199 (2001).

    Article  CAS  Google Scholar 

  25. Jaleco, A. C. et al. Genetic modification of human B-cell development: B-cell development is inhibited by the dominant-negative helix-loop-helix factor Id3. Blood 94, 2637–2646 (1999).

    CAS  PubMed  Google Scholar 

  26. Yokota, Y. et al. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature 397, 702–706 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Ikawa, T., Fujimoto, S., Kawamoto, H., Katsura, Y. & Yokota, Y. Commitment to natural killer cells requires the helix-loop-helix inhibitor Id2. Proc. Natl Acad. Sci. USA 98, 5164–5169 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Blom, B. et al. Disruption of αβ but not of γδ T-cell development by overexpression of the helix-loop-helix protein Id3 in committed T-cell progenitors. EMBO J. 18, 2793–2802 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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 

  30. Allman, D., Punt, J. A., Izon, D. J., Aster, J. C. & Pear, W. S. An invitation to T and more: notch signaling in lymphopoiesis. Cell 109, S1–S11 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. De Smedt, M. et al. Active form of Notch imposes T-cell fate in human progenitor cells. J. Immunol. 169, 3021–3029 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Pui, J. C. et al. Notch1 expression in early lymphopoiesis influences B- versus T-lineage determination. Immunity 11, 299–308 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Jaleco, A. C. et al. Differential effects of Notch ligands Delta-1 and Jagged-1 in human lymphoid differentiation. J. Exp. Med. 194, 991–1002 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Han, W., Ye, Q. & Moore, M. A. A soluble form of human Delta-like-1 inhibits differentiation of hematopoietic progenitor cells. Blood 95, 1616–1625 (2000).

    CAS  PubMed  Google Scholar 

  35. Leonard, W. J. Cytokines and immunodeficiency diseases. Nature Rev. Immunol. 1, 200–208 (2001).

    Article  CAS  Google Scholar 

  36. von Freeden-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  CAS  PubMed  Google Scholar 

  37. 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 

  38. DiSanto, J. P., Rieux Laucat, F., Dautry Varsat, A., Fischer, A. & de Saint Basile, G. Defective human interleukin-2 receptor γ chain in an atypical X chromosome-linked severe combined immunodeficiency with peripheral T cells. Proc. Natl Acad. Sci. USA 91, 9466–9470 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Noguchi, M. et al. Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73, 147–157 (1993).This paper was the first to show that the most common form of severe combined immunodeficiency in humans, characterized by an absence of T cells and NK cells (X-linked SCID), is caused by mutations in the γ-chain of the IL-2 receptor.

    Article  CAS  PubMed  Google Scholar 

  40. Puel, A., Ziegler, S. F., Buckley, R. H. & Leonard, W. J. Defective IL7R expression in T-B+NK+ severe combined immunodeficiency. Nature Genet. 20, 394–397 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Stephan, V. et al. Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells. N. Engl. J. Med. 335, 1563–1567 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Hacein-Bey-Abina, S. et al. Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N. Engl. J. Med. 346, 1185–1193 (2002).This exciting paper shows the successful gene therapy of patients suffering from X-linked SCID. An intact γc DNA was introduced into bone-marrow cells of these patients using retroviral gene transfer. After transplantation of the gene-modified bone-marrow cells, T cells were produced that carried the transgene. T cells from the treated patients were functionally normal and able to mediate immunoprotection.

    Article  CAS  PubMed  Google Scholar 

  43. Russell, S. M. et al. Interaction of IL-2R β and γc chains with Jak1 and Jak3: implications for XSCID and XCID. Science 266, 1042–1045 (1994).

    Article  CAS  PubMed  Google Scholar 

  44. Venkitaraman, A. R. & Cowling, R. J. Interleukin-7 induces the association of phosphatidylinositol 3-kinase with the α chain of the interleukin-7 receptor. Eur. J. Immunol. 24, 2168–2175 (1994).

    Article  CAS  PubMed  Google Scholar 

  45. Lin, J. X. et al. The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13 and IL-15. Immunity 2, 331–339 (1995).

    Article  CAS  PubMed  Google Scholar 

  46. Pallard, C. et al. Distinct roles of the phosphatidylinositol 3-kinase and STAT5 pathways in IL-7-mediated development of human thymocyte precursors. Immunity 10, 525–535 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Lin, J. X. & Leonard, W. J. The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene 19, 2566–2576 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Macchi, P. et al. Mutations of Jak-3 gene in patients with autosomal severe combined immunodeficiency. Nature 377, 65–68 (1995).

    Article  CAS  PubMed  Google Scholar 

  49. Russell, S. M. et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 270, 797–800 (1995).References 48 and 49 show that JAK3-deficient patients lack T cells and NK cells, as do γc-deficient patients. These studies imply that IL-7 and IL-15 drive T- and NK-cell development, respectively, through JAK3.

    Article  CAS  PubMed  Google Scholar 

  50. Nosaka, T. et al. Defective lymphoid development in mice lacking Jak3. Science 270, 800–802 (1995).

    Article  CAS  PubMed  Google Scholar 

  51. Candeias, S., Muegge, K. & Durum, S. K. IL-7 receptor and VDJ recombination: trophic versus mechanistic actions. Immunity 6, 501–508 (1997).

    Article  CAS  PubMed  Google Scholar 

  52. Maki, K., Sunaga, S. & Ikuta, K. The V–J recombination of T-cell receptor-γ genes is blocked in interleukin-7 receptor-deficient mice. J. Exp. Med. 184, 2423–2427 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Durum, S. K. et al. Interleukin-7 receptor control of T-cell receptor γ gene rearrangement: role of receptor-associated chains and locus accessibility. J. Exp. Med. 188, 2233–2241 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ye, S. K. et al. Induction of germline transcription in the TCRγ locus by Stat5: implications for accessibility control by the IL-7 receptor. Immunity 11, 213–223 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Sleasman, J. W. et al. Arrested rearrangement of TCR Vβ genes in thymocytes from children with X-linked severe combined immunodeficiency disease. J. Immunol. 153, 442–448 (1994).

    CAS  PubMed  Google Scholar 

  56. Okamoto, Y., Douek, D. C., McFarland, R. D. & Koup, R. A. Effects of exogenous interleukin-7 on human thymus function. Blood 99, 2851–2858 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Plum, J., De Smedt, M., Leclercq, G., Verhasselt, B. & Vandekerckhove, B. Interleukin-7 is a critical growth factor in early human T-cell development. Blood 88, 4239–4245 (1996).

    CAS  PubMed  Google Scholar 

  58. Kraft, D. L., Weissman, I. L. & Waller, E. K. Differentiation of CD3−4−8− human fetal thymocytes in vivo: characterization of a CD3−4+8− intermediate. J. Exp. Med. 178, 265–277 (1993).

    Article  CAS  PubMed  Google Scholar 

  59. Alvarez-Vallina, L., Gonzalez, A., Gambon, F., Kreisler, M. & Diaz-Espada, F. Delimitation of the proliferative stages in the human thymus indicates that cell expansion occurs before the expression of CD3 (T-cell receptor). J. Immunol. 150, 8–16 (1993).

    CAS  PubMed  Google Scholar 

  60. Ramiro, A. R., Trigueros, C., Marquez, C., San, M. J. & Toribio, M. L. Regulation of pre-T-cell receptor (pTα-TCRβ) gene expression during human thymic development. J. Exp. Med. 184, 519–530 (1996).

    Article  CAS  PubMed  Google Scholar 

  61. 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 

  62. Hoffman, E. S. et al. Productive T-cell receptor β-chain gene rearrangement: coincident regulation of cell cycle and clonality during development in vivo. Genes Dev. 10, 948–962 (1996).

    Article  CAS  PubMed  Google Scholar 

  63. Anderson, S. J., Abtraham, K. M., Nakayama, T., Singer, A. & Perlmutter, R. M. Inhibition of T-cell receptor β-chain gene rearrangement by overexpression of the non-receptor protein tyrosine kinase p56lck. EMBO J. 11, 4877–4886 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Carrasco, Y. R., Trigueros, C., Ramiro, A. R., De Yebenes, V. G. & Toribio, M. L. β-selection is associated with the onset of CD8β chain expression on CD4+CD8αα+ pre-T cells during human intrathymic development. Blood 94, 3491–3498 (1999).

    CAS  PubMed  Google Scholar 

  65. Aifantis, I. et al. On the role of the pre-T cell receptor in αβ versus γδ T-lineage commitment. Immunity 9, 649–655 (1998).

    Article  CAS  PubMed  Google Scholar 

  66. Herblot, S., Steff, A. M., Hugo, P., Aplan, P. D. & Hoang, T. SCL and LMO1 alter thymocyte differentiation: inhibition of E2A-HEB function and pre-Tα chain expression. Nature Immunol. 1, 138–144 (2000).

    Article  CAS  Google Scholar 

  67. Reizis, B. & Leder, P. The upstream enhancer is necessary and sufficient for the expression of the pre-T-cell receptor α gene in immature T lymphocytes. J. Exp. Med. 194, 979–990 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Verschuren, M. C. et al. Preferential rearrangements of the T cell receptor-δ-deleting elements in human T cells. J. Immunol. 158, 1208–1216 (1997).

    CAS  PubMed  Google Scholar 

  69. Trigueros, C. et al. Identification of a late stage of small noncycling pTα-pre-T cells as immediate precursors of T-cell receptor αβ+ thymocytes. J. Exp. Med. 188, 1401–1412 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Verschuren, M. C. M., Blom, B., Spits, H. & van Dongen, J. J. M. PjA-Bp expression and T-cell receptor δ deletion during human T-cell development. Int. Immunol. 10, 1873–1880 (1998).

    Article  CAS  PubMed  Google Scholar 

  71. Brändle, D., Müller, S., Müller, C., Hengartner, H. & Pircher, H. Regulation of RAG-1 and CD69 expression in the thymus during positive and negative selection. Eur. J. Immunol. 24, 145–151 (1994).

    Article  PubMed  Google Scholar 

  72. Vanhecke, D., Leclercq, G., Plum, J. & Vandekerckhove, B. Characterization of distinct stages during differentiation of human CD69+ thymocytes and identification of thymic emigrants. J. Immunol. 155, 1862–1870 (1995).

    CAS  PubMed  Google Scholar 

  73. Vanhecke, D. et al. MHC class II molecules are required for initiation of positive selection but not during terminal differentiation of human CD4 single-positive thymocytes. J. Immunol. 158, 3730–3737 (1997).

    CAS  PubMed  Google Scholar 

  74. Vanhecke, D. et al. Human thymocytes become lineage committed at an early postselection CD69+ stage, before the onset of functional maturation. J. Immunol. 159, 5973–5983 (1997).

    CAS  PubMed  Google Scholar 

  75. Vanhecke, D. et al. Differentiation to T-helper cells in the thymus: gradual acquisition of T-helper cell function by CD3+CD4+ cells. J. Immunol. 155, 4711–4718 (1995).

    CAS  PubMed  Google Scholar 

  76. Reith, W. & Mach, B. The bare lymphocyte syndrome and the regulation of MHC expression. Annu. Rev. Immunol. 19, 331–373 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Henwood, J. et al. Human T-cell repertoire generation in the absence of MHC class II expression results in a circulating CD4+CD8− population with altered physicochemical properties of complementarity-determining region 3. J. Immunol. 156, 895–906 (1996).

    CAS  PubMed  Google Scholar 

  78. Cardell, S. et al. CD1-restricted CD4+ T cells in major histocompatibility complex class II-deficient mice. J. Exp. Med. 182, 993–1004 (1995).

    Article  CAS  PubMed  Google Scholar 

  79. Arpaia, E., Shahar, M., Dadi, H., Cohen, A. & Roifman, C. M. Defective T-cell receptor signaling and CD8+ thymic selection in humans lacking ZAP-70 kinase. Cell 76, 947–958 (1994).

    Article  CAS  PubMed  Google Scholar 

  80. Chan, A. C. et al. ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency. Science 264, 1599–1601 (1994).

    Article  CAS  PubMed  Google Scholar 

  81. Elder, M. E. et al. Human severe combined immunodeficiency due to a defect in ZAP-70, a T-cell tyrosine kinase. Science 264, 1596–1599 (1994).

    Article  CAS  PubMed  Google Scholar 

  82. Gelfand, E. W., Weinberg, K., Mazer, B. D., Kadlecek, T. A. & Weiss, A. Absence of ZAP-70 prevents signaling through the antigen receptor on peripheral-blood T cells but not on thymocytes. J. Exp. Med. 182, 1057–1065 (1995).

    Article  CAS  PubMed  Google Scholar 

  83. Noraz, N. et al. Alternative antigen receptor (TCR) signaling in T cells derived from ZAP-70-deficient patients expressing high levels of Syk. J. Biol. Chem. 275, 15832–15838 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Roberts, J. L., Volkman, D. J. & Buckley, R. H. Modified MHC restriction of donor-origin T cells in humans with severe combined immunodeficiency transplanted with haploidentical bone-marrow stem cells. J. Immunol. 143, 1575–1579 (1989).

    CAS  PubMed  Google Scholar 

  85. Roncarolo, M. G. et al. Antigen recognition by MHC-incompatible cells of a human mismatched chimera. J. Exp. Med. 168, 2139–2152 (1988).

    Article  CAS  PubMed  Google Scholar 

  86. Spits, H., Touraine, J. L., Yssel, H., De Vries, J. E. & Roncarolo, M. G. Presence of host-reactive and MHC-restricted T cells in a transplanted severe combined immunodeficient (SCID) patient suggest positive selection and absence of clonal deletion. Immunol. Rev. 116, 101–116 (1990).

    Article  CAS  PubMed  Google Scholar 

  87. Vandekerckhove, B. A. et al. Thymic selection of the human T-cell receptor Vβ repertoire in SCID-hu mice. J. Exp. Med. 176, 1619–1624 (1992).

    Article  CAS  PubMed  Google Scholar 

  88. Vandekerckhove, B. A., Namikawa, R., Bacchetta, R. & Roncarolo, M. G. Human hematopoietic cells and thymic epithelial cells induce tolerance via different mechanisms in the SCID-hu mouse thymus. J. Exp. Med. 175, 1033–1043 (1992).

    Article  CAS  PubMed  Google Scholar 

  89. Schols, D., Vandekerckhove, B., Jones, D. & Roncarolo, M. G. IL-2 reverses human T-cell unresponsiveness induced by thymic epithelium in SCID-hu mice. J. Immunol. 152, 2198–2206 (1994).

    CAS  PubMed  Google Scholar 

  90. Bacchetta, R. et al. Chimerism and tolerance to host and donor in severe combined immunodeficiencies transplanted with fetal liver stem cells. J. Clin. Invest. 91, 1067–1078 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Schiff, S. E. & Buckley, R. H. Modified responses to recipient and donor B cells by genetically donor T cells from human haploidentical bone-marrow chimeras. J. Immunol. 138, 2088–2094 (1987).

    CAS  PubMed  Google Scholar 

  92. Bacchetta, R. et al. High levels of interleukin-10 production in vivo are associated with tolerance in SCID patients transplanted with HLA-mismatched hematopoietic stem cells. J. Exp. Med. 179, 493–502 (1994).

    Article  CAS  PubMed  Google Scholar 

  93. Stephens, L. A., Mottet, C., Mason, D. & Powrie, F. Human CD4+CD25+ thymocytes and peripheral T cells have immune suppressive activity in vitro. Eur. J. Immunol. 31, 1247–1254 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Annunziato, F. et al. Phenotype, localization and mechanism of suppression of CD4+CD25+ human thymocytes. J. Exp. Med. 196, 379–387 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Bensinger, S. J., Bandeira, A., Jordan, M. S., Caton, A. J. & Laufer, T. M. Major histocompatibility complex class-II-positive cortical epithelium mediates the selection of CD4+25+ immunoregulatory T cells. J. Exp. Med. 194, 427–438 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Jordan, M. S. et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nature Immunol. 2, 301–306 (2001).

    Article  CAS  Google Scholar 

  97. Zippelius, A. et al. Thymic selection generates a large T-cell pool recognizing a self-peptide in humans. J. Exp. Med. 195, 485–494 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Coulie, P. G. et al. A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J. Exp. Med. 180, 35–42 (1994).

    Article  CAS  PubMed  Google Scholar 

  99. Kawakami, Y. et al. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc. Natl Acad. Sci. USA 91, 3515–3519 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ogg, G. S., Rod Dunbar, P., Romero, P., Chen, J. L. & Cerundolo, V. High frequency of skin-homing melanocyte-specific cytotoxic T lymphocytes in autoimmune vitiligo. J. Exp. Med. 188, 1203–1208 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kong, F., Chen, C. H. & Cooper, M. D. Thymic function can be accurately monitored by the level of recent T-cell emigrants in the circulation. Immunity 8, 97–104 (1998).The first paper to show that TCR excision circles (TRECs) are present in recent thymic emigrants. These studies were carried out in the chicken, for which cell-surface markers that define recent thymic emigrants are available.

    Article  CAS  PubMed  Google Scholar 

  102. Douek, D. C. et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 396, 690–695 (1998).This paper reports that TRECs are present in recent thymic emigrants in humans. Using this TREC analysis, the authors show that the thymus of aged individuals is still able to produce new T cells.

    Article  CAS  PubMed  Google Scholar 

  103. Hazenberg, M. D., Verschuren, M. C., Hamann, D., Miedema, F. & van Dongen, J. J. T-cell receptor excision circles as markers for recent thymic emigrants: basic aspects, technical approach and guidelines for interpretation. J. Mol. Med. 79, 631–640 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. Ye, P. & Kirschner, D. E. Reevaluation of T-cell receptor excision circles as a measure of human recent thymic emigrants. J. Immunol. 168, 4968–4979 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Sempowski, G. et al. Effect of thymectomy on human peripheral blood T-cell pools in myasthenia gravis. J. Immunol. 166, 2808–2817 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Kimmig, S. et al. Two subsets of naive T-helper cells with distinct T-cell receptor excision circle content in human adult peripheral blood. J. Exp. Med. 195, 789–794 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. McFarland, R. D., Douek, D. C., Koup, R. A. & Picker, L. J. Identification of a human recent thymic emigrant phenotype. Proc. Natl Acad. Sci. USA 97, 4215–4220 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. George, A. J. & Ritter, M. A. Thymic involution with ageing: obsolescence or good housekeeping? Immunol. Today 17, 267–272 (1996).

    Article  CAS  PubMed  Google Scholar 

  109. Flores, K. G., Li, J., Sempowski, G. D., Haynes, B. F. & Hale, L. P. Analysis of the human thymic perivascular space during aging. J. Clin. Invest. 104, 1031–1039 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Steinmann, G. G., Klaus, B. & Muller-Hermelink, H. K. The involution of the ageing human thymic epithelium is independent of puberty. A morphometric study. Scand. J. Immunol. 22, 563–575 (1985).

    Article  CAS  PubMed  Google Scholar 

  111. Haynes, B. F. et al. Analysis of the adult thymus in reconstitution of T lymphocytes in HIV-1 infection. J. Clin. Invest. 103, 453–460 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Haynes, B. F., Markert, M. L., Sempowski, G. D., Patel, D. D. & Hale, L. P. The role of the thymus in immune reconstitution in aging, bone-marrow transplantation and HIV-1 infection. Annu. Rev. Immunol. 18, 529–560 (2000).An excellent review of age-dependent involution of the thymus and the role of the thymus in clinical settings that are associated with T-cell depletion.

    Article  CAS  PubMed  Google Scholar 

  113. Bertho, J. M. et al. Phenotypic and immunohistological analyses of the human adult thymus: evidence for an active thymus during adult life. Cell. Immunol. 179, 30–40 (1997).

    Article  CAS  PubMed  Google Scholar 

  114. Jamieson, B. D. et al. Generation of functional thymocytes in the human adult. Immunity 10, 569–575 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. Patel, D. D. et al. Thymic function after hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N. Engl. J. Med. 342, 1325–1332 (2000).

    Article  CAS  PubMed  Google Scholar 

  116. Myers, L. A., Patel, D. D., Puck, J. M. & Buckley, R. H. Hematopoietic stem-cell transplantation for severe combined immunodeficiency in the neonatal period leads to superior thymic output and improved survival. Blood 99, 872–878 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Mackall, C. L. et al. Age, thymopoiesis and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N. Engl. J. Med. 332, 143–149 (1995).It is shown here that whereas in young children after chemotherapy, regenerating T cells are thymus derived, in older individuals, the newly appearing T cells are derived mainly from pre-existing memory T cells.

    Article  CAS  PubMed  Google Scholar 

  118. Heitger, A. et al. Essential role of the thymus to reconstitute naive (CD45RA+) T-helper cells after human allogeneic bone-marrow transplantation. Blood 90, 850–857 (1997).

    CAS  PubMed  Google Scholar 

  119. Douek, D. C. et al. Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet 355, 1875–1881 (2000).

    Article  CAS  PubMed  Google Scholar 

  120. Roux, E. et al. Recovery of immune reactivity after T-cell-depleted bone-marrow transplantation depends on thymic activity. Blood 96, 2299–2303 (2000).In this paper, it is shown that whereas pre-existing memory T cells appear relatively early after bone-marrow transplantation, 2–3 years after transplantation, naive T cells with a broad TCR repertoire appear. Together with reference 119 , these data imply that after chemotherapy and bone-marrow transplantation, the thymus of some adults can produce new T cells eventually.

    CAS  PubMed  Google Scholar 

  121. Arlettaz, L. et al. CD45 isoform phenotypes of human T cells: CD4+CD45RA−RO+ memory T cells re-acquire CD45RA without losing CD45RO. Eur. J. Immunol. 29, 3987–3994 (1999).

    Article  CAS  PubMed  Google Scholar 

  122. McCune, J. M. et al. High prevalence of thymic tissue in adults with human immunodeficiency virus-1 infection. J. Clin. Invest. 101, 2301–2308 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Berzins, S. P., Boyd, R. L. & Miller, J. F. The role of the thymus and recent thymic migrants in the maintenance of the adult peripheral lymphocyte pool. J. Exp. Med. 187, 1839–1848 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Hazenberg, M. D. et al. T-cell receptor excision circle and T-cell dynamics after allogeneic stem-cell transplantation are related to clinical events. Blood 99, 3449–3453 (2002).

    Article  CAS  PubMed  Google Scholar 

  125. Bonyhadi, M. L. et al. HIV induces thymus depletion in vivo. Nature 363, 728–732 (1993).

    Article  CAS  PubMed  Google Scholar 

  126. Aldrovandi, G. M. et al. The SCID-hu mouse as a model for HIV-1 infection. Nature 363, 732–736 (1993).References 125 and 126 show for the first time, using a SCID-hu mouse model, that HIV-1 can have a marked impact on thymic T-cell development.

    Article  CAS  PubMed  Google Scholar 

  127. Jamieson, B. D., Uittenbogaart, C. H., Schmid, I. & Zack, J. A. High viral burden and rapid CD4+ cell depletion in human immunodeficiency virus type-1-infected SCID-hu mice suggest direct viral killing of thymocytes in vivo. J. Virol. 71, 8245–8253 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Jamieson, B. D., Pang, S., Aldrovandi, G. M., Zha, J. & Zack, J. A. In vivo pathogenic properties of two clonal human immunodeficiency virus type 1 isolates. J. Virol. 69, 6259–6264 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Berkowitz, R. D. et al. R5 strains of human immunodeficiency virus type 1 from rapid progressors lacking X4 strains do not possess X4-type pathogenicity in human thymus. J. Virol. 73, 7817–7822 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Kourtis, A. P. et al. Early progression of disease in HIV-infected infants with thymus dysfunction. N. Engl. J. Med. 335, 1431–1436 (1996).

    Article  CAS  PubMed  Google Scholar 

  131. Pedroza Martins, L. et al. Impact of cytokines on replication in the thymus of primary HIV-1 isolates from infants. J. Virol. 76, 6929–6943 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Stoddart, C. A. et al. Impaired replication of protease inhibitor-resistant HIV-1 in human thymus. Nature Med. 7, 712–718 (2002).

    Article  CAS  Google Scholar 

  133. Napolitano, L. A. et al. Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis. Nature Med. 7, 73–79 (2001).

    Article  CAS  PubMed  Google Scholar 

  134. Fry, T. J. et al. A potential role for interleukin-7 in T-cell homeostasis. Blood 97, 2983–2990 (2001).

    Article  CAS  PubMed  Google Scholar 

  135. Teixeira, L. et al. Poor CD4 T-cell restoration after suppression of HIV-1 replication may reflect lower thymic function. Aids 15, 1749–1756 (2001).

    Article  CAS  PubMed  Google Scholar 

  136. Steffens, C. M. et al. T-cell receptor excision circle (TREC) content following maximum HIV suppression is equivalent in HIV-infected and HIV-uninfected individuals. Aids 15, 1757–1764 (2001).

    Article  CAS  PubMed  Google Scholar 

  137. Franco, J. M. et al. T-cell repopulation and thymic volume in HIV-1-infected adult patients after highly active antiretroviral therapy. Blood 99, 3702–3706 (2002).

    Article  CAS  PubMed  Google Scholar 

  138. Douek, D. C. et al. Evidence for increased T-cell turnover and decreased thymic output in HIV infection. J. Immunol. 167, 6663–6668 (2001).

    Article  CAS  PubMed  Google Scholar 

  139. Hazenberg, M. D. et al. Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T-cell population in HIV-1 infection. Nature Med. 6, 1036–1042 (2000).References 138 and 139 are representative of widely opposing views on the interpretation of TREC analyses using T cells of HIV-1-infected individuals and what these analyses say about the function of the thymus in HIV-1 infection.

    Article  CAS  PubMed  Google Scholar 

  140. Zhang, L. et al. Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy. J. Exp. Med. 190, 725–732 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Gorochov, G. et al. Perturbation of CD4+ and CD8+ T-cell repertoires during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy. Nature Med. 4, 215–221 (1998).

    Article  CAS  PubMed  Google Scholar 

  142. Walker, R. E. et al. Peripheral expansion of pre-existing mature T cells is an important means of CD4+ T-cell regeneration HIV-infected adults. Nature Med. 4, 852–856 (1998).

    Article  CAS  PubMed  Google Scholar 

  143. Hazenberg, M. D., Hamann, D., Schuitemaker, H. & Miedema, F. T-cell depletion in HIV-1 infection: how CD4+ T cells go out of stock. Nature Immunol. 1, 285–289 (2000).

    Article  CAS  Google Scholar 

  144. Fry, T. J. & Mackall, C. L. Interleukin-7: from bench to clinic. Blood 99, 3892–3904 (2002).

    Article  CAS  PubMed  Google Scholar 

  145. McCune, J. M. et al. The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science 241, 1632–1639 (1988).

    Article  CAS  PubMed  Google Scholar 

  146. Kingston, R., Jenkinson, E. & Owen, J. J. T. A single stem cell can recolonize an embryonic thymus, producing phenotypically distinct T-cell populations. Nature 317, 811–813 (1985).

    Article  CAS  PubMed  Google Scholar 

  147. Fisher, A. G. et al. Human thymocyte development in mouse organ cultures. Int. Immunol. 2, 571–578 (1990).

    Article  CAS  PubMed  Google Scholar 

  148. Sánchez, M. J., Spits, H., Lanier, L. L. & Philips, J. H. Human natural-killer-cell-committed thymocytes and their relationship to the T-cell lineage. J. Exp. Med. 178, 1857–1866 (1993).

    Article  PubMed  Google Scholar 

  149. Res, P. et al. CD34+CD38dim cells in the human thymus can differentiate into T, natural killer and dendritic cells but are distinct from stem cells. Blood 87, 5196–5206 (1996).

    CAS  PubMed  Google Scholar 

  150. Galy, A., Travis, M., Cen, D. & Chen, B. Human T, B, natural killer and dendritic cells arise from a common bone-marrow progenitor subset. Immunity 3, 459–473 (1995).

    Article  CAS  PubMed  Google Scholar 

  151. De Villartay, J. P., Hockett, R. D., Coran, D., Korsmeyer, S. J. & Cohen, D. I. Deletion of the human T-cell receptor δ-gene by a site-specific recombination. Nature 335, 170–174 (1988).

    Article  CAS  PubMed  Google Scholar 

  152. Kong, F. K., Chen, C. L., Six, A., Hockett, R. D. & Cooper, M. D. T-cell receptor gene deletion circles identify recent thymic emigrants in the peripheral T-cell pool. Proc. Natl Acad. Sci. USA 96, 1536–1540 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Res, P. C., Couwenberg, F., Vyth-Dreese, F. A. & Spits, H. Expression of pTα mRNA in a committed dendritic-cell precursor in the human thymus. Blood 94, 2647–2657 (1999).

    CAS  PubMed  Google Scholar 

  154. Radtke, F. et al. Notch1 deficiency dissociates the intrathymic development of dendritic cells and T cells. J. Exp. Med. 191, 1085–1094 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Ramiro, A. R. et al. Differential developmental regulation and functional effects on pre-TCR surface expression of human pTα(a) and pTα(b) spliced isoforms. J. Immunol. 167, 5106–5114 (2001).

    Article  CAS  PubMed  Google Scholar 

  156. Res, P., Blom, B., Hori, T., Weijer, K. & Spits, H. Downregulation of CD1 marks acquisition of functional maturation of human thymocytes and defines a control point in late stages of human T-cell development. J. Exp. Med. 185, 141–151 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I thank A. Berns, C. Mackall, M. L. Toribio, J. Plum, F. Miedema, C. Uittenbogaart and M. Hazenberg for critical reading of the manuscript and suggestions for improvements.

Author information

Authors and Affiliations

  1. Department of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands

    Hergen Spits

Authors
  1. Hergen Spits
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

LocusLink

CCR5

CD1A

CD2

CD3ɛ

CD3ζ

CD4

CD7

CD8

CD27

CD31

CD34

CD45

CD62L

CD69

CD103

CXCR4

DELTA1

E12

γc

GM-CSFR

HEB

ID2

ID3

IL-2

IL-4

IL-7

IL-7Rα

IL-9

IL-15

IL-21

JAK1

JAK3

LCK

Melan-A/MART1

NOTCH1

PI3K

pTα

RAG1

Rag2

STAT5

SYK

ZAP70

OMIM

BLS

DiGeorge syndrome

SCID-X1

Swiss-Prott

GFP

Glossary

THYMIC INVOLUTION

The age-dependent decrease in thymic epithelial volume, which results in decreased production of T cells.

RETROVIRUS-MEDIATED GENE TRANSFER

The introduction of genetic material into cells using a recombinant retrovirus as a vector.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spits, H. Development of αβ T cells in the human thymus. Nat Rev Immunol 2, 760–772 (2002). https://doi.org/10.1038/nri913

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri913

This article is cited by

Search

Advanced 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