Overview of thymus development and decline
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cellular components characteristic of the homeostatic thymic stroma are no
longer maintained, but instead undergo a gradual disorganization of thymic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.
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