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.

T-cell development made simple

Abstract

The thymus is the primary site of T-cell lymphopoiesis. However, the precise molecular interactions that enable the thymus to carry out this function are only recently being elucidated. Although several important molecular players have been identified, including soluble factors, extracellular matrix components, and integral membrane receptors and their ligands, the precise role of these molecules in thymocyte differentiation has yet to be fully characterized. In this regard, the advent of a simple and efficient culture system for the generation of T cells from stem cells, as discussed here, should greatly facilitate the study of T-cell development.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Intrathymic T-cell development.
Figure 2: A simple schematic overview of Notch signalling.
Figure 3: T-cell development made simple: a schematic overview of stem cell–OP9-DL1 cell co-cultures, and potential applications/experimental approaches of this model system.

References

  1. 1

    Miller, J. F. The discovery of thymus function and of thymus-derived lymphocytes. Immunol. Rev. 185, 7–14 (2002).

    CAS  Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

    Petrie, H. T. Role of thymic organ structure and stromal composition in steady-state postnatal T-cell production. Immunol. Rev. 189, 8–19 (2002).

    CAS  Article  Google Scholar 

  4. 4

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

    CAS  Article  Google Scholar 

  5. 5

    Kondo, M., Weissman, I. L. & Akashi, K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661–672 (1997).

    CAS  Article  Google Scholar 

  6. 6

    Allman, D. et al. Thymopoiesis independent of common lymphoid progenitors. Nature Immunol. 4, 168–174 (2003).

    CAS  Article  Google Scholar 

  7. 7

    Igarashi, H., Gregory, S. C., Yokota, T., Sakaguchi, N. & Kincade, P. W. Transcription from the RAG1 locus marks the earliest lymphocyte progenitors in bone marrow. Immunity 17, 117–130 (2002).

    CAS  Article  Google Scholar 

  8. 8

    Hirose, J. et al. A developing picture of lymphopoiesis in bone marrow. Immunol. Rev. 189, 28–40 (2002).

    CAS  Article  Google Scholar 

  9. 9

    Wang, H. & Spangrude, G. J. Aspects of early lymphoid commitment. Curr. Opin. Hematol. 10, 203–207 (2003).

    Article  Google Scholar 

  10. 10

    Henderson, A. J. & Dorshkind, K. In vitro models of B lymphocyte development. Semin. Immunol. 2, 181–187 (1990).

    CAS  PubMed  Google Scholar 

  11. 11

    Anderson, G., Moore, N. C., Owen, J. J. & Jenkinson, E. J. Cellular interactions in thymocyte development. Annu. Rev. Immunol. 14, 73–99 (1996).

    CAS  Article  Google Scholar 

  12. 12

    Godfrey, D. I., Kennedy, J., Suda, T. & Zlotnik, A. A developmental pathway involving four phenotypically and functionally distinct subsets of CD3CD4CD8 triple negative adult mouse thymocytes defined by CD44 and CD25 expression. J. Immunol. 150, 4244–4252 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Ceredig, R. & Rolink, T. A positive look at double-negative thymocytes. Nature Rev. Immunol. 2, 888–897 (2002).

    CAS  Article  Google Scholar 

  14. 14

    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).

    CAS  Article  Google Scholar 

  15. 15

    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).

    CAS  Article  Google Scholar 

  16. 16

    Porritt, H. E., Gordon, K. & Petrie, H. T. Kinetics of steady-state differentiation and mapping of intrathymic-signaling environments by stem cell transplantation in nonirradiated mice. J. Exp. Med. 198, 957–962 (2003).

    CAS  Article  Google Scholar 

  17. 17

    Norment, A. M. & Bevan, M. J. Role of chemokines in thymocyte development. Semin. Immunol. 12, 445–455 (2000).

    CAS  Article  Google Scholar 

  18. 18

    Anderson, G., Jenkinson, E. J., Moore, N. C. & Owen, J. J. T. MHC class II-positive epithelium and mesenchyme cells are both required for T-cell development in the thymus. Nature 362, 70–73 (1993).

    CAS  Article  Google Scholar 

  19. 19

    Kamarck, M. E. & Gottlieb, P. D. Expression of thymocyte surface alloantigens in the fetal mouse thymus in vivo and in organ culture. J. Immunol. 119, 407–415 (1977).

    CAS  PubMed  Google Scholar 

  20. 20

    DeLuca, D., Mandel, T. E., Luckenbach, G. A. & Kennedy, M. M. Tolerance induction by fusion of fetal thymus lobes in organ culture. J. Immunol. 124, 1821–1829 (1980).

    CAS  PubMed  Google Scholar 

  21. 21

    Asamoto, H. & Mandel, T. E. Thymus in mice bearing the Steel mutation. Morphologic studies on fetal, neonatal, organ-cultured, and grafted fetal thymus. Lab. Invest. 45, 418–426 (1981).

    CAS  PubMed  Google Scholar 

  22. 22

    Ceredig, R., Jenkinson, E. J., MacDonald, H. R. & Owen, J. J. Development of cytolytic T lymphocyte precursors in organ-cultured mouse embryonic thymus rudiments. J. Exp. Med. 155, 617–622 (1982).

    CAS  Article  Google Scholar 

  23. 23

    Sekaly, R. P., Ceredig, R. & MacDonald, H. R. Generation of thymocyte subpopulations in organ culture: correlated analysis of Lyt-2 phenotype and cell cycle status by flow microfluorometry. J. Immunol. 131, 1085–1089 (1983).

    CAS  PubMed  Google Scholar 

  24. 24

    Jenkinson, E. J., Franchi, L., Kingston, R. & Owen, J. J. T. Effects of deoxyguanosine on lymphopoiesis in the developing thymus rudiment in vitro: application in the production of chimeric thymus rudiments. Eur. J. Immunol. 12, 583–587 (1982).

    CAS  Article  Google Scholar 

  25. 25

    Jenkinson, E. J. & Owen, J. J. T. T cell differentiation in thymus organ culture. Semin. Immunol. 2, 51–58 (1990).

    CAS  PubMed  Google Scholar 

  26. 26

    Takahama, Y. Differentiation of mouse thymocytes in fetal thymus organ culture. Methods Mol. Biol. 134, 37–46 (2000).

    CAS  PubMed  Google Scholar 

  27. 27

    Jenkinson, E. J. & Anderson, G. Fetal thymic organ cultures. Curr. Opin. Immunol. 6, 293–297 (1994).

    CAS  Article  Google Scholar 

  28. 28

    Lu, L., Xiao, M., Shen, R. N., Grigsby, S. & Broxmeyer, H. E. Enrichment, characterization, and responsiveness of single primitive CD34 human umbilical cord blood hematopoietic progenitors with high proliferative and replating potential. Blood 81, 41–48 (1993).

    CAS  PubMed  Google Scholar 

  29. 29

    Dexter, T. M., Allen, T. D. & Lajtha, L. G. Conditions controlling the proliferation of haemopoietic stem cells in vitro. J. Cell. Physiol. 91, 335–344 (1977).

    CAS  Article  Google Scholar 

  30. 30

    Johnson, G. R. Colony formation in agar by adult bone marrow multipotential hemopoietic cells. J. Cell. Physiol. 103, 371–383 (1980).

    CAS  Article  Google Scholar 

  31. 31

    Kubota, K. & Preisler, H. D. Comparison of agar and methylcellulose culture methods for human erythroid colony formation. Exp. Hematol. 10, 292–299 (1982).

    CAS  PubMed  Google Scholar 

  32. 32

    Landreth, K. S. & Dorshkind, K. Pre-B cell generation potentiated by soluble factors from a bone marrow stromal cell line. J. Immunol. 140, 845–852 (1988).

    CAS  PubMed  Google Scholar 

  33. 33

    Collins, L. S. & Dorshkind, K. A stromal cell line from myeloid long-term bone marrow cultures can support myelopoiesis and B lymphopoiesis. J. Immunol. 138, 1082–1087 (1987).

    CAS  PubMed  Google Scholar 

  34. 34

    Cumano, A., Dorshkind, K., Gillis, S. & Paige, C. J. The influence of S17 stromal cells and interleukin 7 on B cell development. Eur. J. Immunol. 20, 2183–2189 (1990).

    CAS  Article  Google Scholar 

  35. 35

    Kodama, H., Nose, M., Niida, S. & Nishikawa, S. Involvement of the c-kit receptor in the adhesion of hematopoietic stem cells to stromal cells. Exp. Hematol. 22, 979–984 (1994).

    CAS  PubMed  Google Scholar 

  36. 36

    Ueno, H. et al. A stromal cell-derived membrane protein that supports hematopoietic stem cells. Nature Immunol. 4, 457–463 (2003).

    CAS  Article  Google Scholar 

  37. 37

    Nakano, T., Kodama, H. & Honjo, T. Generation of lympho–hematopoietic cells from embryonic stem cells in culture. Science 265, 1098–1101 (1994).

    CAS  Article  Google Scholar 

  38. 38

    Nakano, T., Kodama, H. & Honjo, T. In vitro development of primitive and definitive erythrocytes from different precursors. Science 272, 722–724 (1996).

    CAS  Article  Google Scholar 

  39. 39

    Nakano, T. Lymphohematopoietic development from embryonic stem cells in vitro. Semin. Immunol. 7, 197–203 (1995).

    CAS  Article  Google Scholar 

  40. 40

    Cho, S. K., Bourdeau, A., Letarte, M. & Zúñiga-Pflücker, J. C. Expression and function of CD105 during the onset of hematopoiesis from Flk1+ precursors. Blood 98, 3635–3642 (2001).

    CAS  Article  Google Scholar 

  41. 41

    Cho, S. K. et al. Functional characterization of B lymphocytes generated in vitro from embryonic stem cells. Proc. Natl Acad. Sci. USA 96, 9797–9802 (1999).

    CAS  Article  Google Scholar 

  42. 42

    Nakayama, N., Fang, I. & Elliott, G. Natural killer and B-lymphoid potential in CD34+ cells derived from embryonic stem cells differentiated in the presence of vascular endothelial growth factor. Blood 91, 2283–2295 (1998).

    CAS  PubMed  Google Scholar 

  43. 43

    Carlyle, J. R. et al. Identification of a novel developmental stage marking lineage commitment of progenitor thymocytes. J. Exp. Med. 186, 173–182 (1997).

    CAS  Article  Google Scholar 

  44. 44

    Williams, N. S. et al. Differentiation of NK1. 1+, Ly49+ NK cells from flt3+ multipotent marrow progenitor cells. J. Immunol. 163, 2648–2656 (1999).

    CAS  Google Scholar 

  45. 45

    Pear, W. S. & Radtke, F. Notch signaling in lymphopoiesis. Semin. Immunol. 15, 69–79 (2003).

    CAS  Article  Google Scholar 

  46. 46

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

    CAS  Article  Google Scholar 

  47. 47

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

    CAS  Article  Google Scholar 

  48. 48

    Washburn, T. et al. Notch activity influences the αβ versus γδ T cell lineage decision. Cell 88, 833–843 (1997).

    CAS  Article  Google Scholar 

  49. 49

    Wolfer, A., Wilson, A., Nemir, M., MacDonald, H. R. & Radtke, F. Inactivation of Notch1 impairs VDJβ rearrangement and allows pre-TCR-independent survival of early αβ lineage thymocytes. Immunity 16, 869–879 (2002).

    CAS  Article  Google Scholar 

  50. 50

    Fowlkes, B. J. & Robey, E. A. A reassessment of the effect of activated Notch1 on CD4 and CD8 T cell development. J. Immunol. 169, 1817–1821 (2002).

    CAS  Article  Google Scholar 

  51. 51

    Izon, D. J. et al. Notch1 regulates maturation of CD4+ and CD8+ thymocytes by modulating TCR signal strength. Immunity 14, 253–264 (2001).

    CAS  Article  Google Scholar 

  52. 52

    Robey, E. et al. An activated form of Notch influences the choice between CD4 and CD8 T cell lineages. Cell 87, 483–492 (1996).

    CAS  Article  Google Scholar 

  53. 53

    Deftos, M. L. & Bevan, M. J. Notch signaling in T cell development. Curr. Opin. Immunol. 12, 166–172 (2000).

    CAS  Article  Google Scholar 

  54. 54

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

    CAS  Article  Google Scholar 

  55. 55

    Han, H. et al. Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision. Int. Immunol. 14, 637–645 (2002).

    CAS  Article  Google Scholar 

  56. 56

    Hozumi, K., Abe, N., Chiba, S., Hirai, H. & Habu, S. Active form of notch members can enforce T lymphopoiesis on lymphoid progenitors in the monolayer culture specific for B cell development. J. Immunol. 170, 4973–4979 (2003).

    CAS  Article  Google Scholar 

  57. 57

    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).

    CAS  Article  Google Scholar 

  58. 58

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

    CAS  Article  Google Scholar 

  59. 59

    Anderson, G., Pongracz, J., Parnell, S. & Jenkinson, E. J. Notch ligand-bearing thymic epithelial cells initiate and sustain Notch signaling in thymocytes independently of T cell receptor signaling. Eur. J. Immunol. 31, 3349–54 (2001).

    CAS  Article  Google Scholar 

  60. 60

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

    CAS  Article  Google Scholar 

  61. 61

    Harman, B. C., Jenkinson, E. J. & Anderson, G. Microenvironmental regulation of Notch signalling in T cell development. Semin. Immunol. 15, 91–97 (2003).

    CAS  Article  Google Scholar 

  62. 62

    Felli, M. P. et al. Expression pattern of Notch1, 2 and 3 and Jagged1 and 2 in lymphoid and stromal thymus components: distinct ligand-receptor interactions in intrathymic T cell development. Int. Immunol. 11, 1017–1025 (1999).

    CAS  Article  Google Scholar 

  63. 63

    Kaneta, M. et al. A role for pref-1 and HES-1 in thymocyte development. J. Immunol. 164, 256–264 (2000).

    CAS  Article  Google Scholar 

  64. 64

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

    CAS  Article  Google Scholar 

  65. 65

    Lehar, S. M. & Bevan, M. J. T cell development in culture. Immunity 17, 689–692 (2002).

    CAS  Article  Google Scholar 

  66. 66

    Koch, U., Yuan, J. S., Harper, J. A. & Guidos, C. J. Fine-tuning Notch1 activation by endocytosis and glycosylation. Semin. Immunol. 15, 99–106 (2003).

    CAS  Article  Google Scholar 

  67. 67

    Shutter, J. R. et al. Dll4, a novel Notch ligand expressed in arterial endothelium. Genes Dev. 14, 1313–1318 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Dorsch, M. et al. Ectopic expression of Delta4 impairs hematopoietic development and leads to lymphoproliferative disease. Blood 100, 2046–2055 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Poussier, P. & Julius, M. Speculation on the lineage relationships among CD4 CD8+ gut-derived T cells and their role(s). Semin. Immunol. 11, 293–303 (1999).

    CAS  Article  Google Scholar 

  70. 70

    Lancrin, C. et al. Major T cell progenitor activity in bone marrow-derived spleen colonies. J. Exp. Med. 195, 919–929 (2002).

    CAS  Article  Google Scholar 

  71. 71

    Garcia-Ojeda, M. E., Dejbakhsh-Jones, S., Weissman, I. L. & Strober, S. An alternate pathway for T cell development supported by the bone marrow microenvironment: recapitulation of thymic maturation. J. Exp. Med. 187, 1813–1823 (1998).

    CAS  Article  Google Scholar 

  72. 72

    Wilson, A., Ferrero, I., MacDonald, H. R. & Radtke, F. Cutting edge: an essential role for Notch-1 in the development of both thymus-independent and -dependent T cells in the gut. J. Immunol. 165, 5397–5400 (2000).

    CAS  Article  Google Scholar 

  73. 73

    Williams, G. T., Kingston, R., Owen, M. J., Jenkinson, E. J. & Owen, J. J. T. A single micromanipulated stem cell gives rise to multiple T-cell receptor gene rearrangements in the thymus in vitro. Nature 324, 63–64 (1986).

    CAS  Article  Google Scholar 

  74. 74

    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).

    CAS  Article  Google Scholar 

  75. 75

    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).

    CAS  Article  Google Scholar 

  76. 76

    McManus, M. T. & Sharp, P. A. Gene silencing in mammals by small interfering RNAs. Nature Rev. Genet. 3, 737–747 (2002).

    CAS  Article  Google Scholar 

  77. 77

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

    CAS  Article  Google Scholar 

  78. 78

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

    CAS  Article  Google Scholar 

  79. 79

    Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signaling: cell fate control and signal integration in development. Science 284, 770–776 (1999).

    CAS  Article  Google Scholar 

  80. 80

    Taniguchi, Y. et al. Notch receptor cleavage depends on but is not directly executed by presenilins. Proc. Natl Acad. Sci. USA 99, 4014–4019 (2002).

    CAS  Article  Google Scholar 

  81. 81

    Wu, L. et al. MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nature Genet. 26, 484–489 (2000).

    CAS  Article  Google Scholar 

  82. 82

    Kao, H. Y. et al. A histone deacetylase co-repressor complex regulates the Notch signal transduction pathway. Genes Dev. 12, 2269–2277 (1998).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

I thank the Canadian Institutes for Health Research and the National Cancer Institute of Canada for their support. Apologies to all colleagues whose work was not cited owing to space constraints.

Author information

Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

DATABASES

LocusLink

AIRE

CD117

CD25

CD4

CD44

CD8

delta-like 1

delta-like 4

MCSF

Notch 1

Further information

Juan Carlos Zúñiga-Pflücker's homepage

Glossary

AUTOIMMUNE REGULATOR

(AIRE). A transcription factor that promotes the ectopic expression of peripheral tissue-restricted antigens by medullary epithelial cells of the thymus.

NEGATIVE SELECTION

The deletion of self-reactive thymocytes in the thymus. Thymocytes that express T-cell receptors that strongly recognize self-peptide bound to self-MHC molecules undergo apoptosis in response to the signalling generated by high-affinity binding.

OP/OP MICE

These mice are deficient in macrophage colony- stimulating factor (MCSF) owing to a naturally occurring recessive mutation, osteopetrosis (op), in the coding region of the MCSF gene.

POSITIVE SELECTION

The maturation of immature CD4+CD8+ precursor thymocytes induced by T-cell receptor (TCR) signals that result from binding to self-peptide–MHC ligands on thymic epithelial cells. This process selects thymocytes that express TCRs that can interact with self-MHC moelcules.

SMALL INTERFERING RNA

(siRNA). RNA interference (RNAi) is a phenomenon by which the expression of a specific gene is inhibited when a double-stranded complementary RNA (siRNA) is introduced into the organism.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zúñiga-Pflücker, J. T-cell development made simple. Nat Rev Immunol 4, 67–72 (2004). https://doi.org/10.1038/nri1257

Download citation

Further reading

Search

Quick links