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.

Formation of a functional thymus initiated by a postnatal epithelial progenitor cell

Nature volume 441, pages 992–996 (2006)Cite this article

Abstract

The thymus is essential for the generation of self-tolerant effector and regulatory T cells. Intrathymic T-cell development requires an intact stromal microenvironment, of which thymic epithelial cells (TECs) constitute a major part1,2,3. For instance, cell-autonomous genetic defects of forkhead box N1 (Foxn1)4 and autoimmune regulator (Aire)5 in thymic epithelial cells cause primary immunodeficiency and autoimmunity, respectively. During development, the thymic epithelial rudiment gives rise to two major compartments, the cortex and medulla. Cortical TECs positively select T cells6, whereas medullary TECs are involved in negative selection of potentially autoreactive T cells7. It has long been unclear whether these two morphologically and functionally distinct types of epithelial cells arise from a common bi-potent progenitor cell8 and whether such progenitors are still present in the postnatal period. Here, using in vivo cell lineage analysis in mice, we demonstrate the presence of a common progenitor of cortical and medullary TECs after birth. To probe the function of postnatal progenitors, a conditional mutant allele of Foxn1 was reverted to wild-type function in single epithelial cells in vivo. This led to the formation of small thymic lobules containing both cortical and medullary areas that supported normal thymopoiesis. Thus, single epithelial progenitor cells can give rise to a complete and functional thymic microenvironment, suggesting that cell-based therapies could be developed for thymus disorders.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: Examples of cell clusters observed in lineage tracing analysis.
Figure 2: A revertable Foxn1 allele ( Foxn1SA2).
Figure 3: Postnatal thymopoiesis in Foxn1SA2/Foxn1SA2;hK14 ::Cre-ERT2 mice.

References

  1. Boehm, T., Bleul, C. C. & Schorpp, M. Genetic dissection of thymus development in mouse and zebrafish. Immunol. Rev. 195, 15–27 (2003)

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Nehls, M. et al. Two genetically separable steps in the differentiation of thymic epithelium. Science 272, 886–889 (1996)

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Anderson, M. S. et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 298, 1395–1401 (2002); published online 10 October 2002 (doi: 10.1126/science.1075958)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Hogquist, K. A. & Bevan, M. J. The nature of the peptide/MHC ligand involved in positive selection. Semin. Immunol. 8, 63–68 (1996)

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Blackburn, C. C. et al. One for all and all for one: thymic epithelial stem cells and regeneration. Trends Immunol. 23, 391–395 (2002)

    Article  CAS  PubMed  Google Scholar 

  9. Nehls, M., Pfeifer, D., Schorpp, M., Hedrich, H. & Boehm, T. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 372, 103–107 (1994)

    Article  ADS  CAS  PubMed  Google Scholar 

  10. Blackburn, C. C. et al. The nu gene acts cell-autonomously and is required for differentiation of thymic epithelial progenitors. Proc. Natl Acad. Sci. USA 93, 5742–5746 (1996)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cunningham-Rundles, C. & Ponda, P. P. Molecular defects in T- and B-cell primary immunodeficiency diseases. Nature Rev. Immunol. 5, 880–892 (2005)

    Article  CAS  Google Scholar 

  12. 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 LTbetaR. J. Exp. Med. 198, 757–769 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Akiyama, T. et al. Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 308, 248–251 (2005); published online 10 February 2005 (doi: 10.1126/science.1105677)

    Article  ADS  CAS  PubMed  Google Scholar 

  14. Bennett, A. R. et al. Identification and characterization of thymic epithelial progenitor cells. Immunity 16, 803–814 (2002)

    Article  CAS  PubMed  Google Scholar 

  15. Gill, J., Malin, M., Hollander, G. A. & Boyd, R. Generation of a complete thymic microenvironment by MTS24(+ ) thymic epithelial cells. Nature Immunol. 3, 635–642 (2002); advance online publication 17 June 2002 (doi:10.1038/ni812)

    Article  CAS  Google Scholar 

  16. Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001); published online 27 March 2001 (doi: 10.1186/1471-213x-1-4)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li, M. et al. Skin abnormalities generated by temporally controlled RXRalpha mutations in mouse epidermis. Nature 407, 633–636 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Vassar, R., Rosenberg, M., Ross, S., Tyner, A. & Fuchs, E. Tissue-specific and differentiation-specific expression of a human K14 keratin gene in transgenic mice. Proc. Natl Acad. Sci. USA 86, 1563–1567 (1989)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rodewald, H. R., Paul, S., Haller, C., Bluethmann, H. & Blum, C. Thymus medulla consisting of epithelial islets each derived from a single progenitor. Nature 414, 763–768 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  20. Soriano, P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nature Genet. 21, 70–71 (1999)

    Article  CAS  PubMed  Google Scholar 

  21. Huth, M., Schlake, T. & Boehm, T. Transposon-induced splicing defect in the rat nude gene. Immunogenetics 45, 282–283 (1997)

    Article  CAS  PubMed  Google Scholar 

  22. Adriani, M. et al. Ancestral founder mutation of the nude (FOXN1) gene in congenital severe combined immunodeficiency associated with alopecia in southern Italy population. Ann. Hum. Genet. 68, 265–268 (2004)

    Article  CAS  PubMed  Google Scholar 

  23. Frank, J. et al. Exposing the human nude phenotype. Nature 398, 473–474 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  24. Pignata, C. et al. Human equivalent of the mouse Nude/SCID phenotype: long-term evaluation of immunologic reconstitution after bone marrow transplantation. Blood 97, 880–885 (2001)

    Article  CAS  PubMed  Google Scholar 

  25. Rossi, S. W., Jenkinson, W. E., Anderson, G. & Jenkinson, E. J. Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature doi:10.1038/nature04813 (this issue)

  26. Schwenk, F., Baron, U., & Rajewsky, K. A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res. 23, 5080–5081 (1995)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nehls, M., Messerle, M., Sirulnik, A., Smith, A. J. & Boehm, T. Two large insert vectors, lambda PS and lambda KO, facilitate rapid mapping and targeted disruption of mammalian genes. Biotechniques 17, 770–775 (1994)

    CAS  PubMed  Google Scholar 

  28. Nehls, M., Pfeifer, D., Micklem, G., Schmoor, C. & Boehm, T. The sequence complexity of exons trapped from the mouse genome. Curr. Biol. 4, 983–989 (1994)

    Article  CAS  PubMed  Google Scholar 

  29. te Riele, H., Maandag, E. R., Clarke, A., Hooper, M. & Berns, A. Consecutive inactivation of both alleles of the pim-1 proto-oncogene by homologous recombination in embryonic stem cells. Nature 348, 649–651 (1990)

    Article  ADS  CAS  PubMed  Google Scholar 

  30. Schorpp, M., Hofmann, M., Dear, T. N. & Boehm, T. Characterization of mouse and human nude genes. Immunogenetics 46, 509–515 (1997)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank A. Maul-Pavicic, S. Groß, C. Sainz-Rueda, A. Haas-Assenbaum, C. Happe, E. Nikolopoulos and M. Konrath for help during various stages of this project, and K. Rajewsky, P. Soriano, P. Chambon, S. Srinivas, K. Eichmann, G. Turchinovich, for mouse lines or reagents. This work was supported by grants from the Deutsche Forschungsgemeinschaft and the Max-Planck Society.

Author information

Author notes

  1. Alexander Reuter

    Present address: Department of Biology, University of Konstanz, D-78457, Konstanz, Germany

Authors and Affiliations

  1. Department of Developmental Immunology, Max-Planck Institute of Immunobiology, Freiburg, Stuebeweg 51, D-79108, Germany

    Conrad C. Bleul, Tatiana Corbeaux, Alexander Reuter & Thomas Boehm

  2. Department of Pathology, University of Freiburg, Freiburg, Breisacher Strasse 115a, D-79110, Germany

    Paul Fisch

  3. Institute of Medical Biometry and Informatics, University of Freiburg, Freiburg, Stefan-Meier-Strasse 26, D-79104, Germany

    Jürgen Schulte Mönting

Authors
  1. Conrad C. Bleul
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tatiana Corbeaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexander Reuter
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paul Fisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jürgen Schulte Mönting
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas Boehm
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Boehm.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg/nature.com/repr intsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

This figure shows the occurrence of yellow cells in the lineage tracing experiment and additional characterization of such genetically marked cells. (PDF 612 kb)

Supplementary Figure 2

This figure shows evidence for a common cortico-medullary progenitor in embryonic thymus. (PDF 264 kb)

Supplementary Figure 3

This figure characterizes mice homozygous for a revertable Foxn1 allele. (PDF 395 kb)

Supplementary Figure 4

This figure shows that reverter mice have a near-normal diversity of TCR repertoire. (PDF 390 kb)

Supplementary Figure 5

This figure characterizes splenocytes in reverter mice. (PDF 570 kb)

Supplementary Figure 6

This figure shows evidence for restoration of a T-cell dependent immune response in reverter mice. (PDF 160 kb)

Supplementary Figure 7

This figure shows that thymopoiesis is normal in reverter mice. (PDF 280 kb)

Supplementary Figure 8

This figure shows that Aire and peripheral self-antigens are expressed in thymic epithelial cells of reverter mice. (PDF 182 kb)

Supplementary Figure 9

This figure shows that thymopoiesis correlates with peripheral T cell reconstitution in reverter mice. (PDF 251 kb)

Supplementary Table 1

This table details the means and variances of yellow cells in thymi of hK14::Cre-ERT2//Rosa26–EYFP mice. (PDF 22 kb)

Supplementary Table 2

This table shows the relationship of proliferation probabilities and cluster size. (PDF 19 kb)

Supplementary Notes

This file details the mathematical model used to simulate the cluster size of epithelial cells derived from progenitor cells. (PDF 58 kb)

Supplementary Methods

This file contains additional details of the methods used in this study. It also contains additional references. (PDF 106 kb)

Supplementary Legends

This file contains legends to Supplementary Figures 1–9 and Supplementary Tables 1 and 2. (PDF 108 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bleul, C., Corbeaux, T., Reuter, A. et al. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 441, 992–996 (2006). https://doi.org/10.1038/nature04850

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04850

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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