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Here we found that splenic T cells exhibit greater functional decline than lymph node T cells within the same aged mouse, prompting investigation into how the aged spleen contributes to T cell aging. Proteomic analysis revealed increased expression of heme detoxification in aged spleen-derived lymphocytes. Exposure to the heme- and iron-rich aged splenic microenvironment induced aging phenotypes in young T cells, including reduced proliferation and CD39 upregulation. T cells survived this hostile niche by maintaining a low labile iron pool, at least in part, via IRP2 downregulation to resist ferroptosis but failed to induce sufficient iron uptake for activation. Iron supplementation enhanced antigen-specific T cell responses in aged mice. This study identifies the aged spleen as a source of hemolytic signals that systemically impair T cell function, underscoring a trade-off between T cell survival and function and implicating iron metabolism in immune aging.<\/jats:p>","DOI":"10.1038\/s43587-025-00981-4","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T09:02:40Z","timestamp":1760691760000},"page":"2247-2262","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Heme and iron toxicity in the aged spleen impairs T cell immunity through iron deprivation"],"prefix":"10.1038","volume":"5","author":[{"given":"David","family":"Ezuz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba","family":"Ombashe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lana","family":"Watad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akmaral","family":"Rakhymzhanova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satyarth","family":"Pandey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orna","family":"Atar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther G.","family":"Meyron-Holtz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6345-2002","authenticated-orcid":false,"given":"Noga","family":"Ron-Harel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"981_CR1","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1038\/s41590-021-00927-z","volume":"22","author":"M Mittelbrunn","year":"2021","unstructured":"Mittelbrunn, M. & Kroemer, G. 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