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While this process is suggested to increase the risk of disease severity in the elderly following infection, direct evidence is lacking. We developed two mouse models that allow us to experimentally prevent or reverse thymic involution. Constitutive Myc expression in thymic epithelial cells (TEC) of middle-aged mice enhanced thymic function, and increased numbers of peripheral na\u00efve CD4 and CD8 T-cells. Inducible Myc expression reversed age-related thymic involution and partially recovered peripheral na\u00efve T-cell numbers. Importantly, improving thymic function in these settings preserved T-cell-dependent antibody responses and significantly reduced T-cell-associated mortality after infection with\n                    <jats:italic>Toxoplasma gondii<\/jats:italic>\n                    . Improved thymic function also rebalanced age-associated alterations in the Treg pool, and mitigated loss of the transcriptional Th1 signature in aged conventional T-cells. Our findings support the value of TEC-focused thymic regeneration strategies for enhancement of T-cell-mediated immunity in the elderly.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3003283","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T17:30:16Z","timestamp":1753723816000},"page":"e3003283","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Enhancing thymic function improves T-cell reconstitution and immune responses in aged mice"],"prefix":"10.1371","volume":"23","author":[{"given":"Abigail","family":"Morales-S\u00e1nchez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieke","family":"Lavaert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie S.","family":"Vacchio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo Ulises","family":"Martinez-Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Egbase","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongge","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross","family":"Lake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Ishikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima Zohra","family":"Braikia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragana","family":"Jankovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjan","family":"Sen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00e9my","family":"Bosselut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4657-8372","authenticated-orcid":true,"given":"Avinash","family":"Bhandoola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E.","family":"Cowan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,7,28]]},"reference":[{"issue":"7","key":"pbio.3003283.ref001","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.it.2009.05.001","article-title":"An evolutionary perspective on the mechanisms of immunosenescence","volume":"30","author":"DP Shanley","year":"2009","journal-title":"Trends Immunol"},{"issue":"13","key":"pbio.3003283.ref002","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2019.05.045","article-title":"Interplay between follistatin, activin A, and BMP4 signaling regulates postnatal thymic epithelial progenitor cell differentiation during aging","volume":"27","author":"A Lepletier","year":"2019","journal-title":"Cell Rep"},{"issue":"7","key":"pbio.3003283.ref003","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1093\/intimm\/dxf042","article-title":"Molecular characterization of the mouse involuted thymus: aberrations in expression of transcription regulators in thymocyte and epithelial compartments","volume":"14","author":"CL Ortman","year":"2002","journal-title":"Int Immunol"},{"issue":"5","key":"pbio.3003283.ref004","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1111\/j.1365-3083.1985.tb01916.x","article-title":"The involution of the ageing human thymic epithelium is independent of puberty. 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