Trends in Immunology
ReviewStructure and function of lymphoid tissuesThymic epithelial cells: working class heroes for T cell development and repertoire selection
Section snippets
Thymic epithelial cells: essential regulators of T cell development and selection
As an exclusive site for the production of T cells bearing the αβ T cell receptor (TCR), the thymus represents a crucial component of the adaptive immune system 1, 2, 3. Migrant lymphoid progenitors that colonise the thymus are triggered to undergo a complex differentiation process that includes phases of proliferation, differentiation and lineage choice. Critically, developing thymocytes are screened for their ability to recognise peptides in the context of major histocompatibility complex
Early T cell development in the thymic cortex
To initiate T cell development, the thymus attracts T lymphoid progenitor cells. Adhesion molecules, including P-selectin that is expressed by thymic endothelial cells [7], and chemokines, including chemokine CC ligand (CCL)21, CCL25, and chemokine CXC ligand (CXCL)12 that are expressed by TECs 8, 9 are involved in progenitor seeding. Progenitors settling in the thymus are exposed to the cytokines, interleukin (IL)-7, and the notch ligand, DL4, which are highly expressed by cTECs and are potent
Attraction to, and formation of, the thymic medulla
Peptide–MHC-mediated TCR engagement in the thymic cortex induces the expression of a chemokine receptor CCR7 in immature T cells 24, 25. Positively selected thymocytes are induced to survive and differentiate into either CD4+CD8− or CD4−CD8+ T cells. Negatively selected cells may also begin expressing CCR7, even though these cells are induced to die nonetheless. In the thymus, the CCR7 ligands (CCR7Ls), CCL19 and CCL21, are highly expressed by mTECs, inducing positively selected thymocytes to
Cortical epithelium
Epithelial cells within the cortex form a reticular network, and are frequently defined on the basis of their positive expression of a panel of markers that includes cytokeratin 8, Ly51, CD205, and MHC class II. More recently, antibodies to the cTEC specific proteosomal subunit β5t and DL4 [41], the latter representing the major Notch ligand for T-lineage commitment 11, 42, have proved to be useful tools to define cTECs further. Relatively few studies have examined the process of cTEC
Emergence and precursor–product relations
In the adult thymus, mTECs can be identified using several cell surface and cytoplasmic markers, which can therefore also be used to investigate the emergence of the mTEC lineage during thymus development. Markers commonly associated with mTECs include cytokeratin 5, the lectin UEA1, CD80, Aire, MTS10, ERTR5, and the tight junction components claudin-3/claudin-4. Flow cytometric analysis identifies mTECs on the basis of the CD45–EpCAM1+Ly51–CD205– phenotype, which can be subdivided further
Concluding remarks
Epithelial cells in the thymus provide functionally distinct areas in the form of the cortex and medulla. By providing these compartments, cTECs and mTECs work together to provide essential signals for specific stages of T cell development. To be a TEC, a complex differentiation process is required, yet understanding of TEC development is still limited. Understanding the processes that control TEC commitment, differentiation, and survival/turnover is a major challenge for future thymus
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