Abstract
T‐cells bearing the αβTCR play a vital role in defending the host against foreign pathogens and malignant transformation of self. Importantly, T‐cells are required to remain tolerant to the host's own cells and tissues in order to prevent self‐reactive responses that can lead to autoimmune disease. T‐cells achieve the capacity for self/nonself discrimination by undergoing a highly selective and rigorous developmental program during their maturation in the thymus. This organ is unique in its ability to support a program of T‐cell development that ensures the establishment of a functionally diverse αβTCR repertoire within the peripheral T‐cell pool. The thymus achieves this by virtue of specialized stromal microenvironments that contain heterogeneous cell types, whose organization and function underpins their ability to educate, support, and screen different thymocyte subsets through various stages of development. These stages range from the entry of early T‐cell progenitors into the thymus, through to the positive and negative selection of the αβTCR repertoire. The importance of the thymus medulla as a site for T‐cell tolerance and the exit of newly generated T‐cells into the periphery is well established. In this review, we summarize current knowledge on the developmental pathways that take place during αβT‐cell development in the thymus. In addition, we focus on the mechanisms that regulate thymic egress and contribute to the seeding of peripheral tissues with newly selected self‐tolerant αβT‐cells.
Highlights
The murine thymus appears during early stages of embryogenesis, arising from the 3rd pharyngeal pouch (3PP) and initially consisting of an endodermal-derived epithelial rudiment surrounded by neural crest-derived mesenchyme.[1,2] Development of the thymus is dependent on the transcription factor Foxn[1], which plays a key role in multiple aspects of thymic epithelial cell (TEC) regulation, including their differentiation, proliferation, and formation of the 3-dimensional TEC network characteristic of thymic parenchyma.[3,4,5] The development of many cell subtypes of the thymic microenvironment is dependent on bidirectional signaling between stromal cells and developing thymocytes
When examining whether the role of IL-4Rα in this process was connected to the known role for the S1P–sphingosine-1-phosphate receptor 1 (S1PR1) axis, we found that cell surface levels of S1PR1 and CD69 on mature thymocytes in WT and Il4ra−/− mice were comparable, suggesting that intrathymic S1P levels were not substantially altered
The regulation of thymus-dependent αβT-cell maturation concludes with the release of those mature, functionally self-tolerant T-cells that have survived the rigors of intrathymic selection events into the systemic circulatory system
Summary
The murine thymus appears during early stages of embryogenesis, arising from the 3rd pharyngeal pouch (3PP) and initially consisting of an endodermal-derived epithelial rudiment surrounded by neural crest-derived mesenchyme.[1,2] Development of the thymus is dependent on the transcription factor Foxn[1], which plays a key role in multiple aspects of thymic epithelial cell (TEC) regulation, including their differentiation, proliferation, and formation of the 3-dimensional TEC network characteristic of thymic parenchyma.[3,4,5] The development of many cell subtypes of the thymic microenvironment is dependent on bidirectional signaling between stromal cells and developing thymocytes. Lineage diversion of CD4+ SP thymocytes, that involves expression of the master transcription factor Foxp[3], results in the formation of nT-Reg that leave the thymus and populate peripheral tissues to limit functional responses of autoreactive T-cells that have escaped negative selection.[35] mTECs are highly specialized in their ability to enforce both thymic tolerance mechanisms. This is at least in part through their ability to ectopically express tissue-restricted antigens (TRAs). During their time within the medulla, mature thymocytes progressively acquire “egress competence” through a program of postselection maturation, which enables them to exit the thymus and enter the periphery
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