Reduced T cell production and loss of thymic epithelial cells (TEC) are hallmarks of immune aging, limiting the diversity of the peripheral T cell repertoire and kinetics and extent of immune recovery following cytoablative therapies, and altering the balance of peripheral naïve and memory T cells. Understanding the mechanisms behind thymus aging may help to identify strategic factors for thymus and T cell regeneration.

We previously identified a postnatal, bipotent, thymic epithelial progenitor cell (TEPC) population (Sca-1^hi, α6^hi, immature cortical TECs) and in conjunction with our transcriptome analysis of the aging thymus, we have identified factors and pathways that may promote or hinder progenitor self-renewal and differentiation. We found aged TEPC had reduced colony forming efficiency compared to their young counterparts, implicating a loss of progenitor function underpins the profound reduction in mature epithelial cells with age.

In addition to intrinsic changes in TECs, we identified an imbalance of factors produced by supporting stromal cells with either agonistic or antagonistic effects. Specifically, we found an age-associated increase in production of stromal cell derived follistatin (FST), a highly potent antagonist of Activin βA, both members of the TGFβ superfamily. Using mouse models of Activin βA deficiency and both in vivo and in vitro 3D culture systems, we demonstrate that Activin βA signalling is required for medullary epithelial cell development. In addition we found an increase in TEC and stromal cell production of bone morphogenic protein (Bmp)-4 during aging. We demonstrate the importance of Bmp4 in the self-renewal of TEPC, Foxn1 expression and maintenance of lineage restricted cortical and medullary epithelial progenitors. The combination of an increased production of Bmp4 holding TECs in a progenitor state, and increased FST production reducing Activin βA signaling for medullary epithelial cell differentiation, leads to a block in mature TEC production during aging.