Paper

Age-related epithelial defects limit thymic function and regeneration

Granadier, David, Rogers, Kelly L., Pe’er, Dana, Ghale, Romina, Kousa, Anastasia I., Flores, Angel E., Argyropoulos, Kimon V., Andrlova, Hana, Gomes, Antonio L.C., da Silva, Marina B., Setty, Manu, Jahn, Lorenz, van den Brink, Marcel R.M., Mazutis, Linas, Lemarquis, Andri, Lee, Nichole, Wimmer, Verena C., Lazrak, Amina, Cooper, Kirsten, Gray, Daniel H.D., Youssef, Salma, Sheridan, Julie M., Nichols, Katherine, Zhao, Kelin, Tsai, Jennifer, Gipson, Brianna, Docampo, Melissa, Manley, Nancy R., Velardi, Enrico, Malard, Florent, Sharma, Roshan, DeWolf, Susan, Sikkema, Lisa, Dudakov, Jarrod A.

2023

Overview

The thymus is essential for establishing adaptive immunity yet undergoes age-related atrophy leading to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age. Focusing on non-hematopoietic stromal cells, and using single-cell and spatial transcriptomics, lineage-tracing, and advanced imaging, we discovered two atypical thymic epithelial cell (TEC) states that emerged with age. Age-associated (aa)TECs formed atypical high-density epithelial clusters that were devoid of thymocytes, an accretion of non-functional thymic tissue that worsened with age and exhibited features of partial epithelial-to-mesenchymal transition (EMT). In silico interaction analysis revealed that aaTEC emergence drew tonic signals from other TEC populations at baseline, acting as a sink for TEC growth factors. Following damage, aaTEC expanded substantially, further perturbing trophic pathways, and correlating with defective regeneration of the involuted thymus. These findings define a unique feature of thymic involution linked to immune aging.

• Publisher: Cold Spring Harbor Laboratory
• Subject: Immunology