Age-related epithelial defects limit thymic function and regeneration

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. ### Competing Interest Statement Dr. Marcel van den Brink has received research support and stock options from Seres Therapeutics and stock options from Notch Therapeutics and Pluto Therapeutics; he has received royalties from Wolters Kluwer; has consulted, received honorarium from or participated in advisory boards for Seres Therapeutics, WindMIL Therapeutics, Rheos Medicines, Merck & Co, Inc., Magenta Therapeutics, Frazier Healthcare Partners, Nektar Therapeutics, Notch Therapeutics, Forty Seven Inc., Priothera, Ceramedix, Lygenesis, Pluto Therapeutics, GlaskoSmithKline, Da Volterra, Vor BioPharma, Novartis (Spouse), Synthekine (Spouse), and Beigene (Spouse); he has IP Licensing with Seres Therapeutics and Juno Therapeutics; and holds a fiduciary role on the Foundation Board of DKMS (a nonprofit organization). The Walter and Eliza Hall Institute of Medical Research receives milestone and royalty payments related to venetoclax. Employees are entitled to receive benefits related to these payments; D.H.D.G reports receiving benefits. DHDG has received research funding from Servier.