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.

  • Opinion
  • Published:

The thymus and T-cell commitment: the right niche for Notch?

Nature Reviews Immunology volume 6, pages 551–555 (2006)Cite this article

Abstract

The current dogma is that the thymus is colonized by progenitors that retain the capacity to generate both T cells and B cells, and that intrathymic Notch signalling determines lineage choice so that T cells, rather than B cells, develop in the thymus. However, evidence is now accumulating to indicate that, at least during fetal life, this is not the case. Rather, it now seems that the fetal thymus is colonized by progenitors that have already made the T-cell versus B-cell lineage choice. We propose an alternative role for Notch signalling in the thymus, which is not to mediate this choice but instead to reveal it by supporting further T-cell differentiation in the thymic microenvironment.

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: Alternative models for the involvement of Notch signalling in T-cell versus B-cell lineage choice.
Figure 2: Anatomical compartmentalization of the first wave of lymphoid progenitors recruited to the thymus.

Similar content being viewed by others

References

  1. 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 

  2. Masuda, K. et al. Thymic anlage is colonized by progenitors restricted to T, NK, and dendritic cell lineages. J. Immunol. 174, 2525–2532 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

  6. Tanigaki, K. et al. Regulation of αβ/γδ T cell lineage commitment and peripheral T cell responses by Notch/RBP-J signaling. Immunity 20, 611–622 (2004).

    Article  CAS  Google Scholar 

  7. Maillard, I. et al. Mastermind critically regulates Notch-mediated lymphoid cell fate decisions. Blood 104, 1696–1702 (2004).

    Article  CAS  Google Scholar 

  8. Koch, U. et al. Subversion of the T/B lineage decision in the thymus by lunatic fringe-mediated inhibition of Notch-1. Immunity 15, 225–236 (2001).

    Article  CAS  Google Scholar 

  9. Anderson, G., Pongrac'z, J., Parnell, S. M. & 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, 3349–3354 (2001).

    Article  CAS  Google Scholar 

  10. Schmitt, T., Ciofani, M., Petrie, H. T. & Zuniga-Pflucker, J. C. Maintenance of T cell specification and differentiation requires recurrent Notch receptor-ligand interactions. J. Exp. Med. 200, 469–479 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Maillard, I., Fang, T. & Pear, W. S. Regulation of lymphoid development, differentiation, and function by the Notch pathway. Annu. Rev. Immunol. 23, 945–974 (2005).

    Article  CAS  Google Scholar 

  15. Zweidler-McKay, P. A. et al. Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies. Blood 106, 3898–3906 (2005).

    Article  CAS  Google Scholar 

  16. 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  Google Scholar 

  17. Balciunaite, G., Ceredig, R. & Rolink, A. G. The earliest subpopulation of mouse thymocytes contains potent T, significant macrophage, and natural killer cell but no B-lymphocyte potential. Blood 105, 1930–1936 (2005).

    Article  CAS  Google Scholar 

  18. Tan, J. B., Visan, I., Yuan, J. S. & Guidos, C. J. Requirement for Notch1 signals at sequential early stages of intrathymic T cell development. Nature Immunol. 6, 671–679 (2005).

    Article  CAS  Google Scholar 

  19. 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 

  20. Zediak, V. P., Maillard, I. & Bhandoola, A. Closer to the source: notch and the nature of thymus-settling cells. Immunity 23, 245–248 (2005).

    Article  CAS  Google Scholar 

  21. Petrie, H. T. & Kincade, P. W. Many roads, one destination for T cell progenitors. J. Exp. Med. 202, 11–13 (2005).

    Article  CAS  Google Scholar 

  22. Schwarz, B. A. & Bhandoola, A. Circulating hematopoietic progenitors with T lineage potential. Nature Immunol. 5, 953–960 (2004).

    Article  CAS  Google Scholar 

  23. Benz, C. & Bluel, 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  Google Scholar 

  24. Katsura, Y. Redefinition of lymphoid progenitors. Nature Rev. Immunol. 2, 127–132 (2002).

    Article  CAS  Google Scholar 

  25. 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 

  26. 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  Google Scholar 

  27. 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  Google Scholar 

  28. Arcangeli, M. L. et al. Extrathymic hemopoietic progenitors committed to T cell differentiation in the adult mouse. J. Immunol. 174, 1980–1988 (2005).

    Article  CAS  Google Scholar 

  29. Lu, M. et al. The earliest thymic progenitors in adults are restricted to T, NK, and dendritic cell lineage and have a potential to form more diverse TCRβ chains than fetal progenitors. J. Immunol. 175, 5848–5856 (2005).

    Article  CAS  Google Scholar 

  30. 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).

    Article  CAS  Google Scholar 

  31. Zuniga-Pflucker, J. C. T-cell development made simple. Nature Rev. Immunol. 4, 67–72 (2004).

    Article  CAS  Google Scholar 

  32. Varnum-Finney, B. et al. The Notch ligand, Jagged-1, influences the development of primitive hematopoietic precursor cells. Blood 91, 4084–4091 (1998).

    CAS  Google Scholar 

  33. Dallas, M. H., Varnum-Finney, B., Delaney, C., Kato, K. & Bernstein, I. D. Density of the Notch ligand Delta1 determines generation of B and T cell precursors from hematopoietic stem cells. J. Exp. Med. 201, 1361–1366 (2005).

    Article  CAS  Google Scholar 

  34. Lehar, S. M., Dooley, J., Farr, A. G. & Bevan, M. J. Notch ligands Delta 1 and Jagged1 transmit distinct signals to T-cell precursors. Blood 105, 1440–1447 (2005).

    Article  CAS  Google Scholar 

  35. Masuda, K. et al. Prethymic T-cell development defined by the expression of paired immunoglobulin-like receptors. EMBO J. 24, 4052–4060 (2005).

    Article  CAS  Google Scholar 

  36. Maillard, I. et al. Notch-dependent T lineage commitment occurs at extrathymic sites following bone marrow transplantation. Blood 107, 3511–3519 (2006).

    Article  CAS  Google Scholar 

  37. Hu, Q. D. et al. F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation. Cell 115, 163–175 (2003).

    Article  CAS  Google Scholar 

  38. Suniara, R. K., Jenkinson, E. J. & Owen, J. J. T. An essential role for thymic mesenchyme in early T cell development. J. Exp. Med. 191, 1051–1056 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The work was supported by an MRC Programme Grant to E.J.J. and G.A.

Author information

Authors and Affiliations

  1. Division of Immunity and Infection, the MRC Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, Birmingham, B15 2TT, UK

    Eric J. Jenkinson, William E. Jenkinson, Simona W. Rossi & Graham Anderson

Authors
  1. Eric J. Jenkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William E. Jenkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Simona W. Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Graham Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric J. Jenkinson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jenkinson, E., Jenkinson, W., Rossi, S. et al. The thymus and T-cell commitment: the right niche for Notch?. Nat Rev Immunol 6, 551–555 (2006). https://doi.org/10.1038/nri1883

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1883

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