The seeding of the thymus is mediated by at least two different pathways: the vasculature-independent embryonic pathway, in which the role of chemokines, such as CC-chemokine ligand 21 (CCL21) and CCL25, has been implicated, and the vasculature-dependent postnatal pathway, in which the adhesive interaction between platelet (P)-selectin and P-selectin glycoprotein ligand 1 is involved.
In the postnatal thymus, double-negative (DN) thymocytes relocate outwards from the cortico–medullary junction to the subcapsular region of the thymic cortex. The role of several chemokine receptors, including CXC-chemokine receptor 4 (CXCR4), CC-chemokine receptor 7 (CCR7) and CCR9, has been described.
Positively selected DP thymocytes relocate from the cortex to the medulla. Chemotaxis through CCR7 expressed by T-cell-receptor-stimulated thymocytes and CCR7 ligands expressed by medullary thymic epithelial cells is involved in this cortex-to-medulla migration.
The medulla is implicated in the establishment of tolerance to tissue-specific antigens and the generation of regulatory T cells.
Chemotaxis through sphingosine-1-phosphate (S1P) receptor 1 expressed by mature single-positive thymocytes and circulating S1P seems to be involved in thymocyte export from the adult thymus.
The generation of multiple microenvironments in the thymus, such as the cortex and the medulla, requires crosstalk signals from developing thymocytes.
Lympho–stromal interactions in multiple microenvironments within the thymus have a crucial role in the regulation of T-cell development and selection. Recent studies have implicated that chemokines that are produced by thymic stromal cells have a pivotal role in positioning developing T cells within the thymus. In this Review, I discuss the importance of stroma-derived chemokines in guiding the traffic of developing thymocytes, with an emphasis on the processes of cortex-to-medulla migration and T-cell-repertoire selection, including central tolerance.
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I would like to thank current and previous members of the laboratory, especially T. Ueno and C. Liu, for their discussion and experiments on thymocyte traffic and thymic micro environments. I also would like to thank M. Kubo and F. Saito for excellent and skillful assistance in the study. Continuous discussions with many colleagues, including G. Hollander, R. Boyd, H. Petrie, G. Anderson, W. van Ewijk, H. Kawamoto, T. Ushiki and A. Singer, have made essential contributions to the framework of the idea reviewed here. Financial support by the MEXT Grant-in-Aid for scientific research and the JSPS Core-to-Core Program is acknowledged.
The author declares no competing financial interests.
- Thymic primordium
The primordium refers to an organ or tissue in its earliest recognizable stage of development. The primordium of the thymus is generated at the ventral aspect of the third pharyngeal pouch as early as embryonic day 10.5 in mice.
- Thymic parenchyma
The parenchyma refers to the functional part of an organ. The parenchyma of the thymus is surrounded by the capsule, the trabeculae and the perivascular spaces.
- Two-photon laser fluorescence microscopy
A fluorescence-imaging technique that takes advantage of the fact that fluorescent molecules can absorb two photons simultaneously during excitation before they emit light. This technique greatly reduces photodamage of living specimens, improves tissue penetration depth, allows the distinct separation between excitation and emission wavelengths, and confines the excitation to a discrete focal point.
- Interstitial fluid
The fluid in the spaces between cells and tissues, outside the lymphatic or cardiovascular systems. Its composition is similar to plasma and lymph.
- Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
(APECED or autoimmune polyendocrine syndrome type 1). APECED is characterized by the presence of two of three clinical symptoms: Addison's disease and/or hypoparathyroidism and/or chronic mucocutaneous candidiasis. It is caused by a mutation in the gene autoimmune regulator (AIRE).
- Hassall's corpuscles
Small clusters or concentric whorls of stratified keratinizing epithelium in the thymic medulla, possibly involved in the negative selection of thymocytes, the generation of regulatory T cells and/or undergoing apoptosis themselves. They are found clearly in the human thymus, but are unclear in the mouse thymus.
- G-protein-coupled receptor
(GPCR). A receptor that is composed of seven membrane-spanning helical segments. These receptors associate with G-proteins, which are a family of trimeric intracellular-signalling proteins with common β- and γ-chains, and one of several α-chains. The α-chain determines the nature of the signal that is transmitted from a ligand-occupied GPCR to downstream effector systems.
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Takahama, Y. Journey through the thymus: stromal guides for T-cell development and selection. Nat Rev Immunol 6, 127–135 (2006). https://doi.org/10.1038/nri1781
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