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Using a conditional transgenic mouse model, we demonstrated that endothelial cells depend on RANK signaling for their cellularity and functional maturation. Decreased RANKL availability during aging resulted in a decline in cellularity and function of both endothelial cells and thymic epithelial cells, contributing to thymic involution. We then found that, whereas RANKL neutralization in young mice mimicked thymic involution, exogenous RANKL treatment in aged mice restored thymic architecture as well as endothelial cell and epithelial cell abundance and functional properties. Consequently, RANKL improved T cell progenitor homing to the thymus and boosted T cell production. This cascade of events resulted in peripheral T cell renewal and effective antitumor and vaccine responses in aged mice. Furthermore, we conducted a proof-of-concept study that showed that RANKL stimulates endothelial cells and epithelial cells in human thymic organocultures. Overall, our findings suggest that targeting the RANK-RANKL axis through exogenous RANKL administration could represent a therapeutic strategy to rejuvenate thymic function and improve T cell immunity during aging.<\/jats:p>","DOI":"10.1126\/scitranslmed.adp3171","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T18:58:53Z","timestamp":1733338733000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":27,"title":["RANKL treatment restores thymic function and improves T cell\u2013mediated immune responses in aged mice"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7613-3668","authenticated-orcid":true,"given":"J\u00e9r\u00e9my C.","family":"Santamaria","sequence":"first","affiliation":[{"name":"Centre d'Immunologie de Marseille-Luminy, CIML, CNRS, INSERM, Aix-Marseille Universit\u00e9, Marseille, Turing Centre for Living Systems, 13288 Marseille Cedex 09, 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