Abstract
The organization of the thymus into distinct cortical and medullary regions enables it to control the step-wise migration and development of immature T-cell precursors. Such a process provides access to specialized cortical and medullary thymic epithelial cells at defined stages of maturation, ensuring the generation of self-tolerant and MHC-restricted conventional CD4+ and CD8+ αβ T cells. The migratory cues and stromal cell requirements that regulate the development of conventional αβ T cells have been well studied. However, the thymus also fosters the generation of several immunoregulatory T-cell populations that form key components of both innate and adaptive immune responses. These include Foxp3+ natural regulatory T cells, invariant γδ T cells, and CD1d-restricted invariant natural killer T cells (iNKT cells). While less is known about the intrathymic requirements of these nonconventional T cells, recent studies have highlighted the importance of the thymus medulla in their development. Here, we review recent findings on the mechanisms controlling the intrathymic migration of distinct T-cell subsets, and relate this to knowledge of the microenvironmental requirements of these cells.
Highlights
The immune system consists of a wide range of specialized cells within tissues that play key roles in the control of pathogen recognition, cellular stress, and tumor surveillance
single positive (SP) thymocyte development has been examined in mice with deficiencies known to disrupt medullary thymic epithelial cell · SP (mTEC) development, such as Relb−/- and Aire−/- mice [17]. Analysis of the latter is of interest and potentially relevant to intrathymic thymocyte migration, as Aire has been linked to the expression of multiple chemokines in the thymic medulla including CCL17, CCL19, CCL21, CCL22, and XCL1 [39, 43, 44]. In both Relb−/- and Aire−/mice, a reduction in mature Qa2+CD69− CD4 SP thymocytes has been reported [17], suggesting that the transition from immature to mature stages in conventional CD4 SP thymocyte development is dependent upon the presence of mTEC via a mechanism linked to their expression of Aire
A single cohort of intravenously transferred immature CD4 SP thymocytes was found to undergo late-stage differentiation extrathymically [24]. These findings suggest that conventional SP thymocyte development can occur independently of interaction with mTECs (Fig. 1), CD11c+ DCs present within Relb-dependent mTECdeficient grafts may influence late-stage thymocyte differentiation [38]
Summary
The thymus medulla fosters generation of natural Treg cells, invariant T Cells and invariant NKT cells : what we learn from intrathymic migration Document Version Publisher's PDF, also known as Version of record Citation for published version (Harvard): Cowan, JE, Jenkinson, WE & Anderson, G 2015, 'The thymus medulla fosters generation of natural Treg cells, invariant T Cells and invariant NKT cells : what we learn from intrathymic migration', European Journal of Immunology, vol 45, no. 3, pp. 652-660. https://doi.org/10.1002/eji.201445108
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