Thymic epithelial cells (TEC) provide most of the specialist functions in the thymus and are critical for the establishment of a microenvironment competent to induce the development of self-tolerant T cells. Paradoxically, from early in life, the thymus gradually becomes atrophic. A central feature is the loss in TEC number, precipitating a progressive decline in immune system function and impacting significantly on healthy ageing. Despite the many advances in medical technology, degeneration of the thymus with age remains poorly understood. Consequently, overcoming the immune deficiencies resulting from damaging cytoablative treatments for cancer therapy or diseases such as HIV, which infect and destroy T cells, remain a major unmet clinical need. In principle two approaches have credence for creating thymic recovery: de novo production or endogenous thymus repair. Essential to both of these, is a knowledge of thymic epithelial progenitor/stem cell (TEPC) biology and alterations in the molecular regulatory networks in TEPC and TEC throughout development, culminating with TEC atrophy. Recent studies have supported the derivation of cortical (cTEC) and medullary (mTEC) epithelial lineages from a common bipotent progenitor in the postnatal thymus, however, the identity of these cells remains elusive.
Through the combination of cellular and molecular characterisation, in vivo turnover and functional analysis by 3D in vivo and in vitro culture systems, we have for the first time identified an adult thymic epithelial progenitor population. We have demonstrated their self-renewal, colony forming potential and importantly, the generation of mature cortical and medullary cell lineages, including the Aire+ medullary subset. The identification of adult thymic epithelial progenitor cells will now enable the field to progress investigations into the molecular regulation of these critical cells during homeostasis, differentiation and regeneration following damage, and degeneration with age. In the longer term, this will enable more targeted approaches for therapeutic thymic regeneration.