Age-related epithelial defects limit thymic function and regeneration Journal Article
| Authors: | Kousa, A. I.; Jahn, L.; Zhao, K.; Flores, A. E.; Acenas, D. 2nd; Lederer, E.; Argyropoulos, K. V.; Lemarquis, A. L.; Granadier, D.; Cooper, K.; D’Andrea, M.; Sheridan, J. M.; 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, V. C.; Rogers, K. L.; DeWolf, S.; Gipson, B.; Gomes, A. L. C.; Setty, M.; Pe’er, D.; Hale, L.; Manley, N. R.; Gray, D. H. D.; van den Brink, M. R. M.; Dudakov, J. A. |
| Article Title: | Age-related epithelial defects limit thymic function and regeneration |
| 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. © The Author(s) 2024. |
| Keywords: | genetics; nonhuman; flow cytometry; forkhead transcription factors; mouse; animal; metabolism; animals; mice; clinical protocol; transcriptomics; wild type; mice, inbred c57bl; c57bl mouse; endothelium cell; regeneration; immunology; immune response; thymus; thymus gland; epithelium cell; epithelial cells; aging; upregulation; schwann cell; adaptive immunity; stroma cell; forkhead transcription factor; thymocyte; thymus function; cell selection; epithelial-mesenchymal transition; single cell analysis; single-cell analysis; epithelial mesenchymal transition; thymocytes; thymus disease; human; male; female; article; differential expression analysis; thymic involution; smooth muscle cell; thymus tissue; whn protein; thymic cortex |
| Journal Title: | Nature Immunology |
| Volume: | 25 |
| Issue: | 9 |
| ISSN: | 1529-2908 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-09-01 |
| Start Page: | 1593 |
| End Page: | 1606 |
| Language: | English |
| DOI: | 10.1038/s41590-024-01915-9 |
| PUBMED: | 39112630 |
| PROVIDER: | scopus |
| PMCID: | PMC11362016 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK author Nicole Lee's first name is misspelled on the original publication -- Source: Scopus |
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