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.

Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus

Abstract

Hassall's corpuscles—first described in the human thymus over 150 years ago1—are groups of epithelial cells within the thymic medulla. The physical nature of these structures differs between mammalian species2. Although Hassall's corpuscles have been proposed to act in both the removal of apoptotic thymocytes3,4 and the maturation of developing thymocytes5 within the thymus, the function of Hassall's corpuscles has remained an enigma. Here we report that human Hassall's corpuscles express thymic stromal lymphopoietin (TSLP). Human TSLP activates thymic CD11c-positive dendritic cells to express high levels of CD80 and CD86. These TSLP-conditioned dendritic cells are then able to induce the proliferation and differentiation of CD4+CD8-CD25- thymic T cells into CD4+CD25+FOXP3+ (forkhead box P3) regulatory T cells. This induction depends on peptide–major histocompatibility complex class II interactions, and the presence of CD80 and CD86, as well as interleukin 2. Immunohistochemistry studies reveal that CD25+CTLA4+ (cytotoxic T-lymphocyte-associated protein 4) regulatory T cells associate in the thymic medulla with activated or mature dendritic cells and TSLP-expressing Hassall's corpuscles. These findings suggest that Hassall's corpuscles have a critical role in dendritic-cell-mediated secondary positive selection of medium-to-high affinity self-reactive T cells, leading to the generation of CD4+CD25+ regulatory T cells within the thymus.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Human TSLP activates thymic CD11c-positive dendritic cells.
Figure 2: TSLP-DCs induce the generation of CD4 + CD8 - CD25 + T cells from CD4 + CD8 - CD25 - thymocytes.
Figure 3: TSLP-DC-induced CD4 + CD25 + cells display features of CD4 + CD25 + T R cells.
Figure 4: CD4 + CD25 + CTLA4 + T R cells are associated with DC-LAMP + CD86 + activated dendritic cells within the thymic medulla.

References

  1. Hassall, A. H. The Microscopic Anatomy of The Human Body in Health and Disease (Samuel Highly, London, 1849)

    Google Scholar 

  2. Farr, A. G., Dooley, J. L. & Erickson, M. Organization of thymic medullary epithelial heterogeneity: implications for mechanisms of epithelial differentiation. Immunol. Rev. 189, 20–27 (2002)

    Article  CAS  Google Scholar 

  3. Blau, J. N. A phagocytic function of Hassall's corpuscles. Nature 208, 564–567 (1965)

    Article  ADS  Google Scholar 

  4. Blau, J. N. & Veall, N. The uptake and localization of proteins, Evans Blue and carbon black in the normal and pathological thymus of the guinea-pig. Immunology 12, 363–372 (1967)

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Senelar, R., Escola, M. J., Escola, R., Serrou, B. & Serre, A. Relationship between Hassall's corpuscles and thymocytes fate in guinea-pig foetus. Biomedicine 24, 112–122 (1976)

    CAS  PubMed  Google Scholar 

  6. Nishio, H., Matsui, K., Tsuji, H., Tamura, A. & Suzuki, K. Immunolocalization of the mitogen-activated protein kinase signalling pathway in Hassall's corpuscles of the human thymus. Acta Histochem. 103, 89–98 (2001)

    Article  CAS  Google Scholar 

  7. He, W., Zhang, Y., Deng, Y. & Kabelitz, D. Induction of TCR-γδ expression on triple-negative (CD3-4-8-) human thymocytes. Comparative analysis of the effects of IL-4 and IL-7. J. Immunol. 154, 3726–3731 (1995)

    CAS  PubMed  Google Scholar 

  8. Le, P. T., Lazorick, S., Whichard, L. P., Haynes, B. F. & Singer, K. H. Regulation of cytokine production in the human thymus: epidermal growth factor and transforming growth factor alpha regulate mRNA levels of interleukin 1α (IL-1α), IL-1β, and IL-6 in human thymic epithelial cells at a post-transcriptional level. J. Exp. Med. 174, 1147–1157 (1991)

    Article  CAS  Google Scholar 

  9. Romagnani, P. et al. High CD30 ligand expression by epithelial cells and Hassall's corpuscles in the medulla of human thymus. Blood 91, 3323–3332 (1998)

    CAS  PubMed  Google Scholar 

  10. Zaitseva, M. et al. Stromal-derived factor 1 expression in the human thymus. J. Immunol. 168, 2609–2617 (2002)

    Article  CAS  Google Scholar 

  11. Annunziato, F. et al. Macrophage-derived chemokine and EBI1-ligand chemokine attract human thymocytes in different stage of development and are produced by distinct subsets of medullary epithelial cells: possible implications for negative selection. J. Immunol. 165, 238–246 (2000)

    Article  CAS  Google Scholar 

  12. Watanabe, N. et al. Human thymic stromal lymphopoietin promotes dendritic cell-mediated CD4+ T cell homeostatic expansion. Nature Immunol. 5, 426–434 (2004)

    Article  CAS  Google Scholar 

  13. Leonard, W. J. TSLP: finally in the limelight. Nature Immunol. 3, 605–607 (2002)

    Article  CAS  Google Scholar 

  14. Soumelis, V. et al. Human epithelial cells trigger dendritic cell-mediated allergic inflammation by producing TSLP. Nature Immunol. 3, 673–680 (2002)

    Article  CAS  Google Scholar 

  15. Friend, S. L. et al. A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells. Exp. Hematol. 22, 321–328 (1994)

    CAS  PubMed  Google Scholar 

  16. Bender, J., Mitchell, T., Kappler, J. & Marrack, P. CD4+ T cell division in irradiated mice requires peptides distinct from those responsible for thymic selection. J. Exp. Med. 190, 367–374 (1999)

    Article  CAS  Google Scholar 

  17. Ernst, B., Lee, D. S., Chang, J. M., Sprent, J. & Surh, C. D. The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11, 173–181 (1999)

    Article  CAS  Google Scholar 

  18. Hsieh, C.-S. et al. Recognition of the peripheral self by naturally arising CD4+CD25+ T cell receptors. Immunity 21, 267–277 (2004)

    Article  CAS  Google Scholar 

  19. Salomon, B. et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431–440 (2000)

    Article  CAS  Google Scholar 

  20. Tai, X., Cowan, M., Feigenbaum, L. & Singer, A. CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differenation independently of interleukin 2. Nature Immunol 6, 152–162 (2005)

    Article  CAS  Google Scholar 

  21. Tarbell, K. V., Yamazaki, S., Olson, K., Toy, P. & Steinman, R. M. CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J. Exp. Med. 199, 1467–1477 (2004)

    Article  CAS  Google Scholar 

  22. Stephens, L. A., Mottet, C., Mason, D. & Powrie, F. Human CD4+CD25+ thymocytes and peripheral T cells have immune suppressive activity in vitro. Eur. J. Immunol. 31, 1247–1254 (2001)

    Article  CAS  Google Scholar 

  23. Sakaguchi, S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22, 531–562 (2004)

    Article  CAS  Google Scholar 

  24. Fontenot, J. D. & Rudensky, A. Y. Molecular aspects of regulatory T cell development. Semin. Immunol. 16, 73–80 (2004)

    Article  CAS  Google Scholar 

  25. Jordan, M. S. et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nature Immunol. 2, 301–306 (2001)

    Article  CAS  Google Scholar 

  26. Apostolou, I., Sarukhan, A., Klein, L. & von Boehmer, H. Origin of regulatory T cells with known specificity for antigen. Nature Immunol. 3, 756–763 (2002)

    Article  CAS  Google Scholar 

  27. Malek, T. R., Yu, A., Vincek, V., Scibelli, P. & Kong, L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rβ-deficient mice: Implications for the nonredundant function of IL-2. Immunity 17, 167–178 (2002)

    Article  CAS  Google Scholar 

  28. Kyewski, B. & Klein, L. Self-antigen presentation by thymic stromal cells: a subtle division of labour. Curr. Opin. Immunol. 12, 179–186 (2000)

    Article  Google Scholar 

  29. von Boehmer, H. Selection of the T-cell repertoire: receptor-controlled checkpoints in T-cell development. Adv. Immunol. 84, 201–238 (2004)

    Article  CAS  Google Scholar 

  30. Bendriss-Vermare, N. et al. Human thymus contains IFN-α-producing CD11c+, myeloid CD11c+, and mature interdigitating dendritic cells. J. Clin. Invest. 107, 835–844 (2001)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. J. Finegold and K. Sternberg for tissue materials; E. Weider, Z. He and K. Ramirez for performing the cell sorting; B. Nortzon and M. Hajek for assistance in the preparation of the manuscript; and L. L. Lanier, S. Ullrich, M. F. Wilkinson and K. Schluns for critical reading and suggestions.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yong-Jun Liu.

Ethics declarations

Competing interests

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

Supplementary information

Supplementary Figures S1–S7

This file contains 7 Supplementary Figures showing that human TSLP expression in Hassall’s corpuscles (Fig. S1), two DC populations in human thymic medulla (Fig. S2), the generation of CD4+CD8-CD25+ cells induced by TSLP-DCs (Fig. S3-5), the molecules that caused TSLP-DCs to induce the generation of CD4+CD25+ TR cells (Fig. S6) and comparative analysis of TSLP-DC–generated CD4+CD25+ T cells from fetal thymus or adult peripheral blood (Fig. S7). (PDF 2093 kb)

Supplementary Figures Legends

Contains text descriptions to accompany the above Supplementary Figures (RTF 23 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Watanabe, N., Wang, YH., Lee, H. et al. Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 436, 1181–1185 (2005). https://doi.org/10.1038/nature03886

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03886

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

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