Thymus Microenvironment: Maintenance, Ageing and Strategies for Thymus Regeneration Following Damage

Abstract The thymus is the major site of T‐lymphocyte production. Nonlymphoid elements, referred to as the thymic stroma, create the thymic microenvironment required to govern differentiation, maturation and tolerance induction of haematopoietic precursors into immune‐competent, nonautoreactive T cells. Thymic epithelial cells (TECs) are integral to thymopoiesis but are affected by ageing. From the onset of puberty, a proportional imbalance of TEC subpopulations coincides with a dramatic numerical loss of developing T cells. By middle‐age numerical loss of TECs accompanies further loss of thymocytes. Ongoing functional impediment of bipotent thymic epithelial progenitor cells (TEPC) has been proposed as one possible underlying cause and is more apparent in males. As such, endogenous recovery following thymic damage, such as from chemotherapy, in middle‐aged males relies heavily on proliferation of residual immature and mature TECs than through homeostatic differentiation of bipotent TEPC evident in middle‐aged females. Various strategies have been proposed to enhance thymus recovery following cytoablative therapies; however, thus far, temporary suppression of sex hormone production appears to have the most wide‐ranging impact on enhancing mature TEC replenishment and thymopoiesis. Key Concepts Thymic epithelial cells are critical for T cell development. Single‐cell transcriptomics and mapping identified more TEC subsets than first realised. Mature thymic medullary epithelial cells are essential for the presentation of self‐antigens for central tolerance induction. During age‐related thymus involution, an imbalance in TEC subsets accompanies the numerical loss of developing T cells from the onset of puberty. Postnatal bipotent thymic epithelial progenitor cells (TEPC) undergo functional attenuation from puberty with sexual dimorphism apparent. Increased reliance on activation and proliferation of enduring single‐lineage cortical and medullary TEC precursors for mature TEC maintenance during ageing. Thymic damage induces homeostatic TEC replenishment via bipotent TEPC in middle‐aged females but is restricted to proliferation and differentiation of single lineage progenitors in middle‐aged males. Temporary suppression of sex hormone production as a strategy for thymus regeneration releases the postpubertal TEPC functional block in males. Therapeutic strategies with clinical potential include adoptive transfer of in vitro generated progenitor T cells, exogenous administration of cytokines and growth factors, and temporary sex steroid inhibition.