Exploring the Details of Thymic Involution

The thymus is necessary for the production of T cells of the adaptive immune system. Active thymic tissue diminishes with age to be replaced with fat, a process known as involution. This reduces the supply of new T cells and is an important contribution to the aging of the immune system. It may be that a better understanding of the fine details of the atrophy of the thymus with age may lead to new approaches to therapy. At present, the few groups working on rejuvenation of the thymus are largely focused on either delivering cells to the thymus or finding ways to upregulate the well-known regulatory pathway for thymic growth relating to the FOXN1 gene. There may be other ways forward.

The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons.

We applied single-cell and spatial transcriptomics, lineage-tracing, and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1.

Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.