Figure 2.

Crumbling architecture with faulty foundations – a proposed model of thymic involution. T-cell development initiates when HSC enter into the thymus. It is still unknown whether the number of HSC entering the thymus is reduced with age and there are still debates over the development potential of these cells. HSC are instructed by the TEC through the developmental pathway of successful T-cell differentiation by a combination of cell–cell contact and soluble factors. In the left diagram, the young thymus is distinctly orientated into the cortex and medulla directing the early and late stages of thymopoiesis, respectively, generating functional T cells. The presence of immunocompetent T cells is imperative to the maintenance of the thymic architecture. However, with increasing age the thymus shrinks, becomes disorganized and the TEC lose defining molecules such as keratin (right diagram) contributing to aberrant T-cell development. As the nature of the relationship between TEC and T cells is symbiotic, these defective T cells have a negative influence on the already age-altered TEC. This leads to a decrease in the number of RTE exiting the thymus and entering the peripheral pool, which in turn results in a constriction of the TCR repertoire in the older individuals by expansion of specific memory clones and decreased naive T-cell numbers. HSC, haematopoietic stem cells; RTE, recent thymic emigrants; TCR, T-cell receptor; TEC, thymic epithelial cells.