胸腺发育
Nature Reviews Immunology 2, (2002)
THYMIC DEVELOPMENT
Going back to our roots
Jenny Buckland
Thymocytes require interactions with many types of epithelial cell in the thymus for their maturation and selection. However, the lineage relationships between these functionally and phenotypically distinct thymic epithelial cells (TECs) have remained unclear. Papers in Immunity and Nature Immunology now provide evidence for a common progenitor cell from which all TECs derive.
The thymic microenvironment is organized into distinct cortical and medullary areas, which are characterized by the presence of thymocyte precursors at defined stages of maturation, mesenchymal cells and several types of specialized epithelial cell. There has been much debate about the origin of TECs, but the lack of cell-specific cell-surface markers has prevented the isolation of putative thymic epithelial stem cells.
Bennett et al. carried out an extensive phenotypic characterization of the cellular composition of the embryonic day (E) 12.5 mouse thymus. Using monoclonal antibodies that are specific for keratin 5, keratin 8, MTS20 and MTS24 (markers that have been shown previously to be expressed by subsets of TECs), and for the differentiation antigens 4F1 and MTS10, several distinct epithelial subsets were identified. The lineage potential of these thymic subsets was assessed directly using a reaggregate fetal thymic organ culture (FTOC) model. Purified MTS20+MTS24+ or MTS20-MTS24- cells were reaggregated, with or without mouse embryonic fibroblasts, for 24-48 hours and then either analysed directly or grafted under the kidney capsule of nude mice, which lack a thymus. MTS20+MTS24+ cells could differentiate into all known types of thymic epithelial cell, attract lymphoid progenitors and support T-cell development in nude mice. The MTS20-MTS24- cells could perform none of these functions. Bennett and colleagues conclude that the MTS20+MTS24+ population has full thymic epithelial progenitor potential and is sufficient to establish a functional thymus in vivo.
Gill et al. also investigated the role of MTS24+ TECs in thymocyte development. E15.5 FTOCs that were depleted of lymphoid cells were treated with purified MTS24-specific monoclonal antibodies before being reconstituted with haematopoietic precursors. Antibody-treated cultures developed 88% fewer thymocytes than control cultures and thymocyte development was blocked at an early stage. In addition, the ability of E15.5 MTS24+ cells to generate functional thymic microenvironments was investigated by assessing the development of ectopic thymi after transplantation of these cells under the kidney capsule of recipient mice. Thymi that had a normal distribution of thymocyte subsets and normal architectural organization developed in mice that received MTS24+CD45- MHC class-II+ cells, whereas no thymi developed in mice that received MTS24-CD45- MHC class-II+ cells. The authors conclude, in agreement with the findings of Bennett et al., that the MTS24+ thymic subset is sufficient to establish and maintain a complete thymic epithelial microenvironment and that these cells have full thymic epithelial progenitor potential.
These studies indicate that all types of thymic epithelial cell derive from a common progenitor cell. It is hoped that further research into MTS24+ TECs will enable thymic epithelial stem cells to be identified.
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