Overview of thymus development and decline

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The thymus originates from endodermal cells from the ventral third pharyngeal pouches during mid-gestation in mouse embryos (1). Once the endodermal cells are specified to become thymic epithelial cells (TECs), a complex set of cellular interactions takes place between TECs, surrounding mesenchyme, and immigrating lymphoid and endothelial progenitor cells. By late gestation, the resulting fetal thymus has a well-developed mesenchymal capsule, contains numerous differentiating thymocytes, has initiated cortical and medullary TEC differentiation programs, and is connected to the blood stream via a network of blood vessels. After birth, the thymus continues to develop and organize its compartmental structure, expanding in size and increasing output of naïve T cells to the peripheral environment (2-4). The thymus then reaches a period of relative homeostasis, in which the complex thymic microenvironments and TECs are maintained in a steady state with turnover of TECs but no net expansion or loss. At some point (although the exact timing of onset is controversial), the thymus enters a period of decline, resulting in thymic atrophy, or involution (5, 6). This process can be thought of as a failure of homeostasis, in that the cellular components characteristic of the homeostatic thymic stroma are no longer maintained, but instead undergo a gradual disorganization of thymic compartments and functional decline. While the mechanisms underlying these processes are as yet poorly characterized and highly controversial, the final product is a clearly deteriorated thymus, with severely reduced output of naïve T cells.

T cell development in the thymus is not a cell autonomous process, but rather requires interactions with TECs that provide signals for T lineage specification/lineage commitment, and thymocyte proliferation, differentiation, survival, and repertoire selection (7, 8). The thymus is organized into regions that contain different populations of TECs and developing thymocytes. The outer compartment is the cortex, the inner region is termed the medulla, and the zone where they meet is the corticomedullary junction (CMJ). Within the mature postnatal thymus, developing thymocytes undergo a stereotypical migration through complex microenvironments, in which they interact with different epithelial and other cells to promote their differentiation and survival (Figure 1) (9, 10). Thymocyte-derived signals are in turn indispensable for development of the unique three-dimensional TEC meshwork and for proper compartment formation and organization. This well-established mutually inductive process is termed "cross-talk" (8, 11, 12), and contributes to the regulation of thymus organogenesis, homeostasis and involution, although the molecular basis for these interactions is poorly understood. Since mechanisms operating in the fetal thymus are required for initial TEC differentiation and compartment organization, they are also obvious candidates for mechanisms that could fail in involution. Thus, to understand thymic degeneration during aging, or devise therapeutic strategies for rebound, it is important to understand the normal ontogeny of the postnatal steady-state thymus including the molecular and cellular mechanisms that contribute to its initial development.