The thymic epithelium arises early in embryonic development from endodermderived structures known as the third pharyngeal pouches. These epithelial tissues form a rudimentary thymus, or thymic anlage. This is colonized by cells of hematopoietic origin that give rise to large numbers of thymocytes, which are committed to the T-cell lineage, and to intrathymic dendritic cells. Thymocytes are not simply passengers within the thymus: they influence the arrangement of the thymic epithelial cells on which they depend for survival, inducing the formation of a reticular epithelial structure that surrounds the developing thymocytes (Fig. 8.17).
The cellular architecture of the human thymus is illustrated in Fig. 8.16. Bone marrow-derived cells are differentially distributed between the thymic cortex and medulla. The cortex contains only immature thymocytes and scattered macrophages, whereas more mature thymocytes, along with dendritic cells, macrophages, and some B cells, are found in the medulla. As will be discussed below, this organization reflects the different developmental events that occur in these two compartments.
The importance of the thymus in immunity was first discovered through experiments on mice; indeed, most of our knowledge of T-cell development in the thymus comes from the mouse. It was found that surgical removal of the thymus (thymectomy) at birth resulted in immunodeficient mice, focusing interest on this organ at a time when the difference between T and B lymphocytes in mammals had not yet been defined. Much evidence, including observations in immunodeficient children, has since confirmed the importance of the thymus in T-cell development. In DiGeorge syndrome in humans and in mice with the nude mutation, the thymus does not form and the affected individual produces B lymphocytes but few T lymphocytes. DiGeorge syndrome is a complex combination of cardiac, facial, endocrine, and immune defects associated with deletions of chromosome 22q11. The nude mutation in mice is due to a defect in the gene for Foxn1, a transcription factor required for terminal epithelial cell differentiation; the name nude was given to this mutation because it also causes hairlessness. Rare cases of a defect in the human FOXN1 gene (which is on chromosome 17) have been associated with T-cell immunodeficiency, absence of a thymus, congenital alopecia, and nail dystrophy.
In mice, the thymus continues to develop for 3–4 weeks after birth, whereas in humans it is fully developed at birth. The rate of T-cell production by the thymus is greatest before puberty. After puberty, the thymus begins to shrink, and the production of new T cells in adults is reduced, although it does continue throughout life. In both mice and humans, removal of the thymus after puberty is not accompanied by any notable loss of T-cell function or numbers. Thus, it seems that once the T-cell repertoire is established, immunity can be sustained without the production of significant numbers of new T cells; the pool of peripheral T cells is instead maintained by long-lived T cells and also by division of some mature T cells.
8-11 Commitment to the T-cell lineage occurs in the thymus following Notch signaling.
T lymphocytes develop from a lymphoid progenitor in the bone marrow that also gives rise to B lymphocytes. Some of these progenitors leave the bone marrow and migrate to the thymus. In the thymus, the progenitor cell receives a signal from thymic epithelial cells that is transduced through a receptor called Notch1 to switch on specific genes. Notch signaling is widely used in animal development to specify tissue differentiation; in lymphocyte development, the Notch signal instructs the precursor to commit to the T-cell lineage rather than the B-cell lineage. Notch signaling is required throughout T-cell development and is also thought to help regulate other T-cell lineage choices, including the α:β versus γ:δ choice.