Age-related epithelial defects limit thymic function and regeneration

Kousa, AI; Jahn, L; Zhao, K; Flores, AE; Acenas, D, 2nd; Lederer, E; Argyropoulos, KV; Lemarquis, AL; Granadier, D; Cooper, K; D&#39;Andrea, M; Sheridan, JM; Tsai, J; Sikkema, L; Lazrak, A; Nichols, K; Lee, N; Ghale, R; Malard, F; Andrlova, H; Velardi, E; Youssef, S; Burgos da Silva, M; Docampo, M; Sharma, R; Mazutis, L; Wimmer, VC; Rogers, KL; DeWolf, S; Gipson, B; Gomes, ALC; Setty, M; Pe&#39;er, D; Hale, L; Manley, NR; Gray, DHD; van den Brink, MRM; Dudakov, JA

Author(s): Kousa, AI; Jahn, L; Zhao, K; Flores, AE; Acenas, D, 2nd; Lederer, E; Argyropoulos, KV; Lemarquis, AL; Granadier, D; Cooper, K; D'Andrea, M; Sheridan, JM; Tsai, J; Sikkema, L; Lazrak, A; Nichols, K; Lee, N; Ghale, R; Malard, F; Andrlova, H; Velardi, E; Youssef, S; Burgos da Silva, M; Docampo, M; Sharma, R; Mazutis, L; Wimmer, VC; Rogers, KL; DeWolf, S; Gipson, B; Gomes, ALC; Setty, M; Pe'er, D; Hale, L; Manley, NR; Gray, DHD; van den Brink, MRM; Dudakov, JA;
Details: Publication Year 2024-08-07,Volume 25,Issue #9,Page 1593-1606
Journal Title: Nature Immunology
Abstract: 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.
Publisher: Springer Nature
Keywords: *Thymus Gland/immunology; Animals; *Epithelial Cells/immunology; *Regeneration/immunology; Mice; *Aging/immunology; *Forkhead Transcription Factors/metabolism/genetics; Epithelial-Mesenchymal Transition/immunology; Mice, Inbred C57BL; Male; Thymocytes/immunology/metabolism; Female; Single-Cell Analysis
Research Division(s): Immunology; Advanced Technology And Biology; Advanced Technology And Biology
PubMed ID: 39112630
Publisher's Version: https://doi.org/10.1038/s41590-024-01915-9
Open Access at Publisher's Site: https://doi.org/10.1038/s41590-024-01915-9
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: s41590-024-01915-9.pdf - (41.73MB, application/pdf)

Creation Date: 2024-08-14 09:49:38

Last Modified: 2024-09-02 11:03:39