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

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.

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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.

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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.

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Correspondence to Thomas Boehm.

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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)

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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

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