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.

  • Article
  • Published:

Generation of a complete thymic microenvironment by MTS24+ thymic epithelial cells

Nature Immunology volume 3, pages 635–642 (2002)Cite this article

Abstract

The epithelial component of the thymic microenvironment is indispensable for the generation of T lymphocytes. Although the heterogeneity of this epithelium is well documented, little is known about precursor-progeny relationships between distinct thymic epithelial lineages. Here we characterized a thymic epithelial cell subpopulation identified by the cell surface glycoprotein MTS24. These cells contained epithelial progenitor cells that were competent and sufficient to fully reconstitute the complex thymic epithelial microenvironment that supported normal T cell development.

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: Biochemical characterization of MTS24.
Figure 2: Expression of MTS24 on primordial pharyngeal endoderm.
Figure 3: Spatial and temporal expression of MTS24 during thymic development.
Figure 4: Flow-cytometric analysis of thymic epithelial cells for MTS24 expression.
Figure 5: Effects of MTS24 mAb on thymocyte differentiation in FTOC.
Figure 6: Generation of a functional epithelial microenvironment by MTS24+ TECs.
Figure 7: Phenotypic characterization of thymic tissue derived from MTS24+ cell aggregates.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Marrack, P. et al. The effect of thymus environment on T cell development and tolerance. Cell 53, 627–634 (1988).

    Article  CAS  Google Scholar 

  3. Cordier, A.C. & Haumond, S.M. Development of thymus, parathyroids, and ultimobranchial bodies in NMRI and nude mice. Am. J. Anat. 157, 227–254 (1980).

    Article  CAS  Google Scholar 

  4. Kirby, M.L. & Waldo, K.L. Role of neural crest in congenital heart disease. Circulation 82, 332–340 (1990).

    Article  CAS  Google Scholar 

  5. Le Douarin, N.M. & Jotereau, F.V. Tracing of cells of the avian thymus through embryonic life in interspecific chimeras. J. Exp. Med. 142, 17–40 (1975).

    Article  CAS  Google Scholar 

  6. Auerbach, R. Morphogenetic interactions in the development of the mouse thymus. Dev. Biol. 2, 271 (1960).

  7. Bockman, D.E. & Kirby, M.L. Dependence of thymus development on derivatives of the neural crest. Science 223, 498–500 (1984).

    Article  CAS  Google Scholar 

  8. Manley, N.R. Thymus organogenesis and molecular mechanisms of thymic epithelial cell differentiation. Semin. Immunol. 12, 421–428 (2000).

    Article  CAS  Google Scholar 

  9. Manley, N.R. & Capecchi, M.R. The role of Hoxa-3 in mouse thymus and thyroid development. Development 121, 1989–2003 (1995).

    CAS  PubMed  Google Scholar 

  10. Su, D.M. & Manley, N.R. Hoxa3 and pax1 transcription factors regulate the ability of fetal thymic epithelial cells to promote thymocyte development. J. Immunol. 164, 5753–5760 (2000).

    Article  CAS  Google Scholar 

  11. Peters, H., Neubüser, A., Kratochwil, K. & Balling, R. Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes. Dev. 12, 2735–2747 (1998).

    Article  CAS  Google Scholar 

  12. Neubuser, A., Koseki, H. & Balling, R. Characterization and developmental expression of Pax9, a paired-box- containing gene related to Pax1. Dev. Biol. 170, 701–716 (1995).

    Article  CAS  Google Scholar 

  13. Conway, S.J., Henderson, D.J. & Copp, A.J. Pax3 is required for cardiac neural crest migration in the mouse: evidence from the splotch (Sp2H) mutant. Development 124, 505–514 (1997).

    CAS  PubMed  Google Scholar 

  14. Itoi, M., Kawamoto, H., Katsura, Y. & Amagai, T. Two distinct steps of immigration of hematopoietic progenitors into the early thymus anlage. Int. Immunol. 13, 1203–1211 (2001).

    Article  CAS  Google Scholar 

  15. 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  CAS  Google Scholar 

  16. Ohuchi, H. et al. FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi- organ development. Biochem. Biophys. Res. Commun. 277, 643–649 (2000).

    Article  CAS  Google Scholar 

  17. Revest, J.M. et al. Fibroblast growth factor receptor 2-IIIb acts upstream of Shh and Fgf4 and is required for limb bud maintenance but not for the induction of Fgf8, Fgf10, Msx1, or Bmp4. Dev. Biol. 231, 47–62 (2001).

    Article  CAS  Google Scholar 

  18. Revest, J.M., Suniara, R.K., Kerr, K., Owen, J.J. & Dickson, C. Development of the thymus requires signaling through the fibroblast growth factor receptor r2-iiib. J. Immunol. 167, 1954–1961 (2001).

    Article  CAS  Google Scholar 

  19. 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).

    Article  CAS  Google Scholar 

  20. Kasai, M. et al. Difference in antigen presentation pathways between cortical and medullary thymic epithelial cells. Eur. J. Immunol. 26, 2101–2107 (1996).

    Article  CAS  Google Scholar 

  21. Kasai, M., Kominami, E. & Mizuochi, T. The antigen presentation pathway in medullary thymic epithelial cells, but not that in cortical thymic epithelial cells, conforms to the endocytic pathway. Eur. J. Immunol. 28, 1867–1876 (1998).

    Article  CAS  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).

    Article  CAS  Google Scholar 

  23. Farr, A., 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).

    Article  CAS  Google Scholar 

  24. Ropke, C., Van Soest, P., Platenburg, P.P. & Van Ewijk, W. A common stem cell for murine cortical and medullary thymic epithelial cells? Dev. Immunol. 4, 149–156 (1995).

    Article  CAS  Google Scholar 

  25. 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).

    Article  CAS  Google Scholar 

  26. Klug, D.B. et al. Transgenic expression of cyclin D1 in thymic epithelial precursors promotes epithelial and T cell development. J. Immunol. 164, 1881–1888 (2000).

    Article  CAS  Google Scholar 

  27. 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  CAS  Google Scholar 

  28. Godfrey, D.I., Izon, D.J., Tucek, C.L., Wilson, T.J. & Boyd, R.L. The phenotypic heterogeneity of mouse thymic stromal cells. Immunology 70, 66–74 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Loeffler, M., Bratke, T., Paulus, U., Li, Y.Q. & Potten, C.S. Clonality and life cycles of intestinal crypts explained by a state dependent stochastic model of epithelial stem cell organization. J. Theor. Biol. 186, 41–54 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  31. Watt, A.J. et al. A gene trap integration provides an early in situ marker for hepatic specification of the foregut endoderm. Mech. Dev. 100, 205–215 (2001).

    Article  CAS  Google Scholar 

  32. Fuchs, E. & Segre, J.A. Stem cells: a new lease on life. Cell 100, 143–155 (2000).

    Article  CAS  Google Scholar 

  33. Zuklys, S. et al. Normal thymic architecture and negative selection are associated with Aire expression, the gene defective in the autoimmune– polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). J. Immunol. 165, 1976–1983 (2000).

    Article  CAS  Google Scholar 

  34. Hollander, G.A. et al. Developmental control point in induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature 373, 350–353 (1995).

    Article  CAS  Google Scholar 

  35. Anderson, G., Anderson, K.L., Tchilian, E.Z., Owen, J.J. & Jenkinson, E.J. Fibroblast dependency during early thymocyte development maps to the CD25+ CD44+ stage and involves interactions with fibroblast matrix molecules. Eur. J. Immunol. 27, 1200–1206 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  38. Oukka, M. et al. Selectivity of the major histocompatibility complex class II presentation pathway of cortical thymic epithelial cell lines. Eur. J. Immunol. 27, 855–859 (1997).

    Article  CAS  Google Scholar 

  39. 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).

    Article  CAS  Google Scholar 

  40. Hare, K.J., Jenkinson, E.J. & Anderson, G. CD69 expression discriminates MHC-dependent and -independent stages of thymocyte positive selection. J. Immunol. 162, 3978–3983 (1999).

    CAS  PubMed  Google Scholar 

  41. Hoffmann, M.W., Allison, J. & Miller, J.F. Tolerance induction by thymic medullary epithelium. Proc. Natl. Acad. Sci. USA 89, 2526–2530 (1992).

    Article  CAS  Google Scholar 

  42. Oukka, M. et al. CD4 T cell tolerance to nuclear proteins induced by medullary thymic epithelium. Immunity 4, 545–553 (1996).

    Article  CAS  Google Scholar 

  43. Simmons, P.J., Levesque, J.P. & Haylock, D.N. Mucin-like molecules as modulators of the survival and proliferation of primitive hematopoietic cells. Ann. NY Acad. Sci. 938, 196–206; discussion 206–207 (2001).

    Article  CAS  Google Scholar 

  44. Lee, Y.N., Kang, J.S. & Krauss, R.S. Identification of a role for the sialomucin CD164 in myogenic differentiation by signal sequence trapping in yeast. Mol. Cell Biol. 21, 7696–7706 (2001).

    Article  CAS  Google Scholar 

  45. Zannettino, A.C. et al. The sialomucin CD164 (MGC-24v) is an adhesive glycoprotein expressed by human hematopoietic progenitors and bone marrow stromal cells that serves as a potent negative regulator of hematopoiesis. Blood 92, 2613–2628 (1998).

    CAS  PubMed  Google Scholar 

  46. Rodewald, H.R. & Fehling, H.J. Molecular and cellular events in early thymocyte development. Adv. Immunol. 69, 1–112 (1998).

    Article  CAS  Google Scholar 

  47. Godfrey, D.I., Izon, D.J., Wilson, T.J., Tucek, C.L. & Boyd, R.L. Thymic stromal elements defined by M. Abs: ontogeny, and modulation in vivo by immunosuppression. Adv. Exp. Med. Biol. 237, 269–275 (1988).

    Article  CAS  Google Scholar 

  48. Berzins, S.P. et al. Thymic shared antigen-2: a novel cell surface marker associated with T cell differentiation and activation. J. Immunol. 162, 5119–5126 (1999).

    CAS  PubMed  Google Scholar 

  49. Bennett, A.R. et al. Identification and characterization of thymic epithelial progenitor cells. Immunity (in press, 2002).

Download references

Acknowledgements

We thank G. Anderson for the introduction to reaggregate thymic organ culture methodology, C. Blackburn for helpful discussion and valuable collaborative input, E. Randle-Barrett for FACS sorting, A. Peter for technical assistance, M. Gaio for secretarial assistance and S. Zuklys and S. Berzins for critical reading of the manuscript. Supported by grants from the Australian National Health and Medical Research Council (to R. B.) and the Swiss National Science Foundation 31-558020.98 (to G. A. H.).

Author information

Authors and Affiliations

  1. Department of Pathology and Immunology, Monash University Medical School, Commercial Road, Prahran, 3181, Melbourne, Australia

    Jason Gill, Mark Malin & Richard Boyd

  2. The Children's University Hospital and Department of Clinical-Biological Sciences, Pediatric Immunology, Basel University, Basel, Switzerland

    Georg A. Holländer

Authors
  1. Jason Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark Malin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Georg A. Holländer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard Boyd
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jason Gill.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gill, J., Malin, M., Holländer, G. et al. Generation of a complete thymic microenvironment by MTS24+ thymic epithelial cells. Nat Immunol 3, 635–642 (2002). https://doi.org/10.1038/ni812

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni812

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