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

Nature volume 436, pages 1181–1185 (2005)Cite this article

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.

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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.

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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.

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  1. Department of Immunology and Center for Cancer Immunology Research, The University of Texas, M. D. Anderson Cancer Center, 7455 Fannin Street, Texas, 77054, Houston, USA

    Norihiko Watanabe, Yi-Hong Wang, Heung Kyu Lee, Tomoki Ito, Yui-Hsi Wang, Wei Cao & Yong-Jun Liu

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  1. Norihiko Watanabe
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Correspondence to Yong-Jun Liu.

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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)

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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

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