The essential role of the thymus is to generate clonally diverse T lymphocytes that can recognize a vast array of foreign proteins presented as peptides on host cells. An essential parallel thymic function is eliminating self-reactive T-cell clones that could damage normal tissue.
The embryonic thymus is formed originally 3rd and 4th pharyngeal pouches which are epithelial cells. These specialized epithelial cells went through the neck region to form thymic lobes in the anterior mediastinum. The epithelial thymus begins to attract hematopoietic stem cells from the circulation around the 8th week of fetal life. Within the epithelial thymus these precursor cells are influenced to proliferate and differentiate along T-lymphocyte lines. This lifelong process begins in the outer cortex of the thymus and the immature thymocytes migrate toward the medullary region as they proliferate and mature.
Cortical regions of the lobules that collectively form the bilateral thymic lobes thus become filled with immature T lymphocytes, the extraordinary clonal diversity of which is manifested by differences in their T-cell receptor (TCR) specificities. Each developing T cell is selected for survival or death depending on the affinity of its receptor for self-peptides, which are presented initially on the surface of cortical epithelial cells.
As maturing thymocytes approach the corticomedullary junction, they encounter macrophages or dendritic cell immigrants that can also present peptide fragments of antigenic proteins. Thymocytes that fail to receive any TCR-mediated signal are programmed to die. Immature thymocytes also receive a death signal if their TCR has relatively high affinity for a self-peptide, whereas moderate affinity for a self-peptide selects for survival. Only 1% or so of the thymic T cells survive this selection process to seed the peripheral lymphoid tissues. After binding to dendritic cells and macrophages via TCR/major histocompatibility complex (MHC) interactions, thymocytes that are negatively selected become sensitive to death signals delivered by fas molecules (CD95) and undergo apoptosis. Thymocytes also possess an array of non-TCR cell-surface glycoproteins that they use to interact with their environment. Progression of thymocyte maturation can be conveniently monitored by the expression of CD4 and CD8 molecules.
Positive Clonal Selection
The most immature thymocytes lack detectable CD4 and CD8. Intermediate-stage thymocytes express both CD4 and CD8; these double-positives predominate in the thymic cortex. Clonal selection occurs during this stage of differentiation, and the CD4 and CD8 molecules play key roles in the selection process. The peptide fragments of antigenic proteins are presented within the alpha-helical grooves of MHC class II and class I molecules. CD4 has an affinity for MHC class II molecules on specialized antigen-presenting cells, whereas the CD8 molecules can bind class I molecules present on all nucleated cells. The CD4 or CD8 molecules thus serve as coreceptors in the positive clonal selection, which leads to the development of either mature CD4+ cells with helper potential or CD8+ T cells with cytotoxic potential. Most of the positively selected helper or cytotoxic T cells exit the thymus via the small blood vessels in the corticomedullary region and via thymic lymphatics. The cellular debris of dying thymocytes undergoes phagocytosis by cortical and medullary macrophages, many of which migrate to epithelial cell swirls of terminally differentiated epithelium called Hassall’s bodies located in the thymic medulla.
The cellular debris of dying thymocytes undergoes phagocytosis by cortical and medullary macrophages, many of which migrate to epithelial cell swirls of terminally differentiated epithelium called Hassall’s bodies located in the thymic medulla. Thymic function can be monitored.
End of Maturation – end of the story
The lymphoid thymus reaches its maximal size of approximately 30 g by around age 1, and it gradually decreases in size thereafter to 3 g or less in most older individuals. Because the thymus-derived T-cell clones may have lifespans of several decades, normally there is little need for constant thymic replenishment. Nevertheless, thymocyte differentiation persists throughout life, albeit usually at low levels, which may vary according to an individual’s hormonal balance and need for T-cell replenishment.