Key Points
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The mature thymus contains two anatomically and functionally distinct stromal compartments, the cortex and medulla. Each compartment contains several phenotypically distinct thymic epithelial-cell (TEC) types. Proper development and organization of these different TECs is essential for thymocyte development and repertoire selection.
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The embryonic origin of the cortical and medullary TEC compartments is controversial. Two models exist: the 'dual-origin' model, in which cortical TECs derive from the pharyngeal ectoderm, whereas medullary TECs derive from the pharyngeal endoderm; and the 'single-origin' model, in which all TECs are of endodermal origin. The dual-origin model has been widely accepted and is the 'textbook' model.
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A recent study has tested the dual- and single-origin models directly in mice, through analysis of the fate of the pharyngeal ectoderm and the potency of the pharyngeal endoderm. These data support a single, endodermal origin for both cortical and medullary TECs, and provide direct evidence against the dual-origin model.
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Recent evidence has also suggested the existence of a common thymic epithelial progenitor cell for both cortical and medullary TECs, and has indicated a clonal origin for individual medullary islets. These studies are consistent with a single-origin model.
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Analysis of the genes that control early thymus organogenesis has identified a Hox–Pax–Eya–Six transcription factor network that is required for initial thymus organogenesis. These factors are co-expressed only in the endoderm, again supporting a single origin for all TECs. The gene(s) responsible for establishing thymus identity, however, has not yet been identified.
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Various signalling pathways, including fibroblast growth factors (Fgfs), Wnts and bone morphogenetic proteins (Bmps), have also been implicated in mediating epithelial–mesenchymal interactions during organogenesis, TEC differentiation and TEC–thymocyte interactions. However, the initiation signal for thymus organogenesis remains elusive.
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Recent studies have challenged the concept that establishment of the cortical and medullary compartments is regulated by 'cross-talk' with lymphocytes, providing evidence that TEC differentiation can be divided into initial lymphocyte-independent and later lymphocyte-dependent stages, and that forkhead box N1 (Foxn1) is required for both of these stages.
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Together, these advances have created a new framework, within which future analysis of thymus organogenesis, TEC differentiation and TEC–thymocyte interactions can be addressed.
Abstract
The mature thymic epithelium is complex, with two major compartments — the cortex and the medulla — each containing several functionally distinct epithelial-cell types. There is considerable debate as to the embryonic origins of these different thymic epithelial-cell subpopulations. The textbook view is a dual origin, with cortical thymic epithelium arising from the ectoderm and medullary thymic epithelium originating in the endoderm. However, the literature has been divided on this issue since it was first considered. In this review, we discuss recent embryological, functional, genetic and molecular data that collectively support a new model of thymus organogenesis and patterning.
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Acknowledgements
C.C.B. is supported by the Leukaemia Research Fund; N.R.M. is supported by the National Institutes of Health, the National Institute of Child Health and Human Development, and the National Institute of Allergy and Infectious Diseases. The authors are also supported by a Biomedical collaboration grant from the Wellcome Trust.
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Glossary
- STROMA
-
Cells that comprise the non-lymphocytic component of the thymus.
- LINEAGE
-
Embryonic origin and fate of cells during normal development.
- ENDODERM
-
The epithelial tube inside the embryo, which gives rise to the small and large intestines, stomach, organs such as the liver and pancreas, and glands, including the thyroid and parathyroid glands.
- NEURAL CREST CELLS
-
Migratory cells derived from the neural tube ectoderm.
- ECTODERM
-
The epithelial sheet that covers the outside of the embryo, which gives rise to skin and hair, for example.
- NUDE
-
A recessive mutation in the forkhead box N1 (Foxn1) gene that causes hairlessness and congenital athymia in mice, rats and humans. Nude individuals lack T cells as a secondary effect of athymia; nude bone marrow is normal.
- POTENCY
-
The differentiative capacity of cells, which might be more extensive than is apparent in normal development.
- FETAL THYMIC ORGAN CULTURE
-
(FTOC). Experimental model for the analysis of T-cell development, typically based on in vitro culture of embryonic day 16.5 mouse fetal thymi.
- REAGGREGATE FETAL THYMIC ORGAN CULTURE
-
(RFTOC). A variation of FTOC used to investigate the role of particular stromal subsets in T-cell development: stromal-cell types purified from fetal thymi are mixed with mesenchymal cells and T-cell progenitors, allowed to reaggregate either on a filter or in a hanging drop, and then cultured in vitro, as for FTOC, before analysis of T-cell development.
- SPLOTCH MICE
-
Mice carrying a mutation in the transcription factor paired box gene 3 (Pax3), which have defects in derivatives of the somatic mesoderm and neural crest.
- COMMON γ-CHAIN
-
(γc). A type I cytokine receptor chain that is shared by the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21. Mutant mice that lack both γc and recombination-activating gene 2 (Rag2) have a severe block in T-, B- and natural killer-cell development; thymocyte development in these mice is blocked at the CD25+ double-negative 2 stage.
- IKAROS
-
This gene encodes a member of a family of zinc-finger transcription factors that are required for the development of all lymphoid lineages, as well as lymph nodes and Peyer's patches. Ikaros-null mutant fetuses lack B cells and T-cell precursors; few Ikaros-null cells enter the fetal thymus, and these fail to develop to the CD25+ double-negative 2 stage.
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Blackburn, C., Manley, N. Developing a new paradigm for thymus organogenesis. Nat Rev Immunol 4, 278–289 (2004). https://doi.org/10.1038/nri1331
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DOI: https://doi.org/10.1038/nri1331
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