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Kousa, A.I.* ; Jahn, L.* ; Zhao, K.* ; Flores, A.E.* ; Acenas, D.* ; 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.A.* ; 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.*

Age-related epithelial defects limit thymic function and regeneration.

Nat. Immunol. 25, 1593-1606 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords T-cell Development; Mesenchymal Transition; Growth-factor; Expression; Midkine; Foxn1; Microenvironment; Pleiotrophin; Enrichment; Maintain
ISSN (print) / ISBN 1529-2908
e-ISSN 1529-2916
Journal Nature Immunology
Quellenangaben Volume: 25, Issue: 9, Pages: 1593-1606 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Heidelberger Platz 3, Berlin, 14197, Germany
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
Grants University of Melbourne Research Training Program Scholarship
Australian National Health and Medical Research Council (NHMRC) Fellowships
NCI Cancer Center
National Institutes of Health
Immunotherapy Integrated Research Center at the Fred Hutchinson Cancer Center
MSK Sawiris Foundation
European Molecular Biology Organization
Bezos Family Foundation
Cuyamaca Foundation
DKMS Foundation for Giving Life
American Society of Hematology
Parker Institute for Cancer Immunotherapy
Cycle for Survival
Lymphoma Foundation
Starr Cancer Consortium
Australian Government NHMRC IRIISS
Cancer Council of Victoria
NHMRC
U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)