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Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium

Abstract

The thymus provides an essential environment for the development of T cells from haemopoietic progenitors. This environment is separated into cortical and medullary regions, each containing functionally distinct epithelial populations that are important at successive stages of T-cell development and selection1,2. However, the developmental origin and lineage relationships between cortical and medullary epithelial cell types remain controversial3. Here we describe a clonal assay to investigate the developmental potential of single, individually selected, thymic epithelial progenitors (marked with enhanced yellow fluorescent protein) developing within the normal architecture of the thymus. Using this approach, we show that cortical and medullary epithelial cells share a common origin in bipotent precursors, providing definitive evidence that they have a single rather than dual germ layer origin during embryogenesis. Our findings resolve a long-standing issue in thymus development, and are important in relation to the development of cell-based strategies for thymus disorders and the possibility of restoring function of the atrophied adult thymus.

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Figure 1: A clonal assay for thymic epithelial progenitors.
Figure 2: A single E12 thymic epithelial cell gives rise to multiple progeny in both cortical and medullary locations in vivo.
Figure 3: Analysis of progeny of single thymic epithelial cells using cortical epithelial markers.
Figure 4: Analysis of progeny of single thymic epithelial cells using medullary epithelial markers.

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)

    CAS  Article  Google Scholar 

  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. Manley, N. R. & Blackburn, C. C. A developmental look at thymus organogenesis: where do the non-hematopoietic cells in the thymus come from? Curr. Opin. Immunol. 15, 225–232 (2003)

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  6. 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)

    ADS  CAS  Article  PubMed  Google Scholar 

  7. Farr, A. G., Nelson, A., Truex, J. & Hosier, S. Epithelial heterogeneity in the murine thymus: a cell surface glycoprotein expressed by subcapsular and medullary epithelium. J. Histochem. Cytochem. 39, 645–653 (1991)

    CAS  Article  PubMed  Google Scholar 

  8. Gill, J., Malin, M. A., Hollander, G. A. & Boyd, R. L. Generation of a complete thymic microenvironment by MTS24(+ ) thymic epithelial cells. Nature Immunol. 3, 635–642 (2002)

    CAS  Article  Google Scholar 

  9. 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)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 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)

    CAS  Article  PubMed  Google Scholar 

  11. Anderson, G., Hare, K. J., Platt, N. & Jenkinson, E. J. Discrimination between maintenance- and differentiation-inducing signals during initial and intermediate stages of positive selection. Eur. J. Immunol. 27, 1838–1842 (1997)

    CAS  Article  PubMed  Google Scholar 

  12. Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4–12 (2001)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Gray, D. H., Chidgey, A. P. & Boyd, R. L. Analysis of thymic stromal cell populations using flow cytometry. J. Immunol. Meth. 260, 15–28 (2002)

    CAS  Article  Google Scholar 

  14. Cordier, A. C. & Haumont, S. M. Development of thymus, parathyroids and ultimo-branchial bodies in NMRI and nude mice. Am. J. Anat. 157, 227–263 (1980)

    CAS  Article  PubMed  Google Scholar 

  15. Gordon, J. et al. Functional evidence for a single endodermal origin for the thymic epithelium. Nature Immunol. 5, 546–553 (2004)

    CAS  Article  Google Scholar 

  16. Jenkinson, W. E., Jenkinson, E. J. & Anderson, G. Differential requirement for mesenchyme in the proliferation and maturation of thymic epithelial progenitors. J. Exp. Med. 198, 325–332 (2003)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Jenkinson, W. E., Rossi, S. W., Jenkinson, E. J. & Anderson, G. Development of functional thymic epithelial cells occurs independently of lymphostromal interactions. Mech. Dev. 122, 1294–1299 (2005)

    CAS  Article  PubMed  Google Scholar 

  18. Yamamoto, N., Tanigaki, K., Han, H., Hiah, H. & Honjo, T. Notch/RBP-J signaling regulates epidermis/hair fate determination of hair follicular stem cells. Curr. Biol. 13, 333–338 (2003)

    CAS  Article  PubMed  Google Scholar 

  19. Jones, P. H., Harper, S. & Watt, F. M. Stem cell patterning and fate in human epidermis. Cell 80, 83–93 (1995)

    CAS  Article  PubMed  Google Scholar 

  20. Wils, E. J. & Cornelissen, J. J. Thymopoiesis following allogeneic stem cell transplantation: new possibilities for improvement. Blood Rev. 19, 89–98 (2005)

    Article  PubMed  Google Scholar 

  21. 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)

    CAS  Article  PubMed  Google Scholar 

  22. Derbinski, J., Schulte, A., Kyewski, B. & Klein, L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nature Immunol. 2, 1032–1039 (2001)

    CAS  Article  Google Scholar 

  23. Smalley, M., Titley, I. & Ashworth, A. An improved definition of mouse mammary epithelial side population cells. Cytotherapy 7, 495–508 (2005)

    Article  Google Scholar 

Download references

Acknowledgements

We thank R. Bird for cell sorting, and S. Parnell and T. Jones for technical assistance. This work was supported by the European Union (FP6 Eurothymaide Constortium) and the Medical Research Council, UK. Author Contributions S.W.R. performed the experiments shown in Figs 23,4, S.W.R. and W.E.J. performed those shown in Fig. 1. G.A. and E.J.J. designed the experiments and wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Graham Anderson.

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Rossi, S., Jenkinson, W., Anderson, G. et al. Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 441, 988–991 (2006). https://doi.org/10.1038/nature04813

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