{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T06:46:50Z","timestamp":1791960410823,"version":"4.3.4"},"reference-count":77,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["ME 5486\/1-2"],"award-info":[{"award-number":["ME 5486\/1-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["ME 5486\/2-1"],"award-info":[{"award-number":["ME 5486\/2-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["F32CA275298"],"award-info":[{"award-number":["F32CA275298"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["K00CA234940"],"award-info":[{"award-number":["K00CA234940"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA284603"],"award-info":[{"award-number":["R01CA284603"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R21AG072205"],"award-info":[{"award-number":["R21AG072205"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA214913"],"award-info":[{"award-number":["R01CA214913"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL128168"],"award-info":[{"award-number":["R01HL128168"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA284372"],"award-info":[{"award-number":["R01CA284372"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA284603"],"award-info":[{"award-number":["R01CA284603"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005190","name":"Melanoma Research Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005190","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001368","name":"V Foundation for Cancer Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001368","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["DP2 AI176139"],"award-info":[{"award-number":["DP2 AI176139"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U19 AI082630"],"award-info":[{"award-number":["U19 AI082630"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003793","name":"Hj\u00e4rt-Lungfonden","doi-asserted-by":"publisher","award":["20180436"],"award-info":[{"award-number":["20180436"]}],"id":[{"id":"10.13039\/501100003793","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2018\u201303232"],"award-info":[{"award-number":["2018\u201303232"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Rullo Family MGH Research Scholar Award"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Aging"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The abundance of diverse naive CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell clones is essential for broad protection against infection and cancer, but how sex and aging jointly shape this compartment remains poorly understood. Here, using mouse models with supporting human data, we uncover a sex-biased mechanism of immune aging in which early male-biased depletion of naive CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells driven by accelerated, antigen-agnostic differentiation into virtual memory cells combines with thymic involution, limiting naive CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell replenishment. These mechanisms led to more rapid lymph node contraction and reduced local naive T cell clone availability in males, limiting cancer antigen recognition. Therapeutic thymus regeneration via androgen ablation repopulated naive CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in lymph nodes, reinvigorated cancer-specific T cell responses and enhanced responsiveness to immune checkpoint blockade in male mice. These findings reveal the impact of sex and age on naive T cell clone abundance in lymph nodes and suggest strategies to restore immune competence in middle-aged men.\n                  <\/jats:p>","DOI":"10.1038\/s43587-026-01238-4","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T09:02:35Z","timestamp":1791536555000},"page":"2126-2142","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lymph node contraction links sex-biased naive CD8+ T cell decline to compromised antigen recognition during middle age"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3816-6255","authenticated-orcid":false,"given":"Lutz","family":"Menzel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4778-8742","authenticated-orcid":false,"given":"Maria","family":"Zschummel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan J.","family":"O\u2019Melia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0973-9499","authenticated-orcid":false,"given":"M\u00e5rten","family":"Sandstedt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9948-7909","authenticated-orcid":false,"given":"Hengbo","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pin-Ji","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingshan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0947-8284","authenticated-orcid":false,"given":"Debattama R.","family":"Sen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lance L.","family":"Munn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Jonasson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3453-9384","authenticated-orcid":false,"given":"Timothy P.","family":"Padera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"key":"1238_CR1","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/s41568-021-00348-y","volume":"21","author":"S Haupt","year":"2021","unstructured":"Haupt, S., Caramia, F., Klein, S. L., Rubin, J. B. & Haupt, Y. Sex disparities matter in cancer development and therapy. Nat. Rev. Cancer 21, 393\u2013407 (2021).","journal-title":"Nat. Rev. Cancer"},{"key":"1238_CR2","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1016\/j.immuni.2022.05.012","volume":"55","author":"C Yang","year":"2022","unstructured":"Yang, C. et al. Androgen receptor-mediated CD8+ T cell stemness programs drive sex differences in antitumor immunity. Immunity 55, 1268\u20131283 (2022).","journal-title":"Immunity"},{"key":"1238_CR3","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1038\/s41586-022-04522-6","volume":"606","author":"X Guan","year":"2022","unstructured":"Guan, X. et al. Androgen receptor activity in T cells limits checkpoint blockade efficacy. Nature 606, 791\u2013796 (2022).","journal-title":"Nature"},{"key":"1238_CR4","doi-asserted-by":"publisher","first-page":"6016","DOI":"10.1016\/j.cell.2024.08.013","volume":"187","author":"Y Chhabra","year":"2024","unstructured":"Chhabra, Y. et al. Sex-dependent effects in the aged melanoma tumor microenvironment influence invasion and resistance to targeted therapy. Cell 187, 6016\u20136034 https:\/\/doi.org\/10.1016\/j.cell.2024.08.013 (2024).","journal-title":"Cell"},{"key":"1238_CR5","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1038\/s41590-024-01828-7","volume":"25","author":"ACY Chen","year":"2024","unstructured":"Chen, A. C. Y. et al. The aged tumor microenvironment limits T cell control of cancer. Nat. Immunol. 25, 1033\u20131045 https:\/\/doi.org\/10.1038\/s41590-024-01828-7 (2024).","journal-title":"Nat. Immunol."},{"key":"1238_CR6","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1038\/s41590-017-0006-x","volume":"19","author":"J Nikolich-\u017dugich","year":"2018","unstructured":"Nikolich-\u017dugich, J. The twilight of immunity: emerging concepts in aging of the immune system. Nat Immunol. 19, 10\u201319 (2018).","journal-title":"Nat Immunol."},{"key":"1238_CR7","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1038\/s41577-018-0001-y","volume":"18","author":"T van den Broek","year":"2018","unstructured":"van den Broek, T., Borghans, J. A. M. & van Wijk, F. The full spectrum of human naive T cells. Nat. Rev. Immunol. 18, 363\u2013373 (2018).","journal-title":"Nat. Rev. Immunol."},{"key":"1238_CR8","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. Hallmarks of T cell aging. Nat. Immunol. 22, 687\u2013698 (2021).","journal-title":"Nat. Immunol."},{"key":"1238_CR9","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1016\/j.ccell.2023.03.009","volume":"41","author":"JA Pai","year":"2023","unstructured":"Pai, J. A. et al. Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade. Cancer Cell 41, 776\u2013790 (2023).","journal-title":"Cancer Cell"},{"key":"1238_CR10","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1038\/s41586-025-09440-x","volume":"649","author":"JL Hor","year":"2026","unstructured":"Hor, J. L. et al. Inhibitory PD-1 axis maintains high-avidity stem-like CD8+ T cells. Nature 649, 194\u2013204 https:\/\/doi.org\/10.1038\/s41586-025-09440-x (2026).","journal-title":"Nature"},{"key":"1238_CR11","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1038\/s41577-023-00884-8","volume":"23","author":"JM Schenkel","year":"2023","unstructured":"Schenkel, J. M. & Pauken, K. E. Localization, tissue biology and T cell state: implications for cancer immunotherapy. Nat. Rev. Immunol. 23, 807\u2013823 (2023).","journal-title":"Nat. Rev. Immunol."},{"key":"1238_CR12","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1016\/j.cell.2025.12.026","volume":"189","author":"E Salazar-Cavazos","year":"2026","unstructured":"Salazar-Cavazos, E. et al. Stochasticity in cancer immunotherapy stems from rare but functionally critical Spark T cells. Cell 189, 1074\u20131085 (2026).","journal-title":"Cell"},{"key":"1238_CR13","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.immuni.2012.02.006","volume":"36","author":"I den Braber","year":"2012","unstructured":"den Braber, I. et al. Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans. Immunity 36, 288\u2013297 (2012).","journal-title":"Immunity"},{"key":"1238_CR14","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1056\/NEJMoa2302892","volume":"389","author":"KA Kooshesh","year":"2023","unstructured":"Kooshesh, K. A., Foy, B. H., Sykes, D. B., Gustafsson, K. & Scadden, D. T. Health consequences of thymus removal in adults. N. Engl. J. Med. 389, 406\u2013417 (2023).","journal-title":"N. Engl. J. Med."},{"key":"1238_CR15","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1038\/s41586-026-10242-y","volume":"652","author":"S Bernatz","year":"2026","unstructured":"Bernatz, S. et al. Thymic health consequences in adults. Nature 652, 986\u2013994 https:\/\/doi.org\/10.1038\/s41586-026-10242-y (2026).","journal-title":"Nature"},{"key":"1238_CR16","doi-asserted-by":"publisher","first-page":"3512","DOI":"10.1016\/j.celrep.2018.05.057","volume":"23","author":"KM Quinn","year":"2018","unstructured":"Quinn, K. M. et al. Age-related decline in primary CD8+ T cell responses is associated with the development of senescence in virtual memory CD8+ T cells. Cell Rep. 23, 3512\u20133524 (2018).","journal-title":"Cell Rep."},{"key":"1238_CR17","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1038\/s41577-020-00457-z","volume":"21","author":"E Velardi","year":"2021","unstructured":"Velardi, E., Tsai, J. J. & van den Brink, M. R. M. T cell regeneration after immunological injury. Nat. Rev. Immunol. 21, 277\u2013291 (2021).","journal-title":"Nat. Rev. Immunol."},{"key":"1238_CR18","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1038\/s41577-024-01119-0","volume":"25","author":"D Granadier","year":"2025","unstructured":"Granadier, D., Acenas, D. & Dudakov, J. A. Endogenous thymic regeneration: restoring T cell production following injury. Nat. Rev. Immunol. 25, 407\u2013424 https:\/\/doi.org\/10.1038\/s41577-024-01119-0 (2025).","journal-title":"Nat. Rev. Immunol."},{"key":"1238_CR19","unstructured":"Surveillance, Epidemiology, and End Results Program. National Cancer Institute https:\/\/seer.cancer.gov\/index.html (2021)."},{"key":"1238_CR20","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-14256-1","volume":"11","author":"MA Durante","year":"2020","unstructured":"Durante, M. A. et al. Single-cell analysis reveals new evolutionary complexity in uveal melanoma. Nat. Commun. 11, 496 (2020).","journal-title":"Nat. Commun."},{"key":"1238_CR21","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/j.cell.2018.10.038","volume":"175","author":"M Sade-Feldman","year":"2018","unstructured":"Sade-Feldman, M. et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175, 998\u20131013 (2018).","journal-title":"Cell"},{"key":"1238_CR22","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1016\/j.cell.2018.11.043","volume":"176","author":"H Li","year":"2019","unstructured":"Li, H. et al. Dysfunctional CD8+ T cells form a proliferative, dynamically regulated compartment within human melanoma. Cell 176, 775\u2013789 (2019).","journal-title":"Cell"},{"key":"1238_CR23","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34877-3","volume":"13","author":"C Zhang","year":"2022","unstructured":"Zhang, C. et al. A single-cell analysis reveals tumor heterogeneity and immune environment of acral melanoma. Nat. Commun. 13, 7250 (2022).","journal-title":"Nat. Commun."},{"key":"1238_CR24","doi-asserted-by":"publisher","first-page":"1525","DOI":"10.1158\/2326-6066.CIR-24-0463","volume":"12","author":"P Georgiev","year":"2022","unstructured":"Georgiev, P. et al. Age-associated contraction of tumor-specific T cells impairs antitumor immunity. Cancer Immunol. Res. 12, 1525\u20131541 https:\/\/doi.org\/10.1158\/2326-6066.CIR-24-0463 (2022).","journal-title":"Cancer Immunol. Res."},{"key":"1238_CR25","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/s41591-018-0266-5","volume":"25","author":"W Scheper","year":"2019","unstructured":"Scheper, W. et al. Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers. Nat. Med. 25, 89\u201394 (2019).","journal-title":"Nat. Med."},{"key":"1238_CR26","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1038\/s41568-019-0235-4","volume":"20","author":"AM van der Leun","year":"2020","unstructured":"van der Leun, A. M., Thommen, D. S. & Schumacher, T. N. CD8+ T cell states in human cancer: insights from single-cell analysis. Nat. Rev. Cancer 20, 218\u2013232 (2020).","journal-title":"Nat. Rev. Cancer"},{"key":"1238_CR27","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1038\/s41577-025-01187-w","volume":"25","author":"E Lanitis","year":"2025","unstructured":"Lanitis, E., Irving, M. & Coukos, G. Tumour-associated vasculature in T cell homing and immunity: opportunities for cancer therapy. Nat. Rev. Immunol. 25, 831\u2013846 (2025).","journal-title":"Nat. Rev. Immunol."},{"key":"1238_CR28","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1126\/science.8171322","volume":"264","author":"P De Togni","year":"1994","unstructured":"De Togni, P. et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264, 703\u2013707 (1994).","journal-title":"Science"},{"key":"1238_CR29","doi-asserted-by":"publisher","DOI":"10.1126\/science.adk6200","volume":"384","author":"L Chi","year":"2024","unstructured":"Chi, L. et al. Sexual dimorphism in skin immunity is mediated by an androgen-ILC2-dendritic cell axis. Science 384, eadk6200 (2024).","journal-title":"Science"},{"key":"1238_CR30","first-page":"520","volume":"17","author":"HR Roth","year":"2014","unstructured":"Roth, H. R. et al. A new 2.5D representation for lymph node detection using random sets of deep convolutional neural network observations. Med. Image Comput. Comput. Assist. Interv. 17, 520\u2013527 (2014).","journal-title":"Med. Image Comput. Comput. Assist. Interv."},{"key":"1238_CR31","doi-asserted-by":"publisher","unstructured":"Rister, B., Shivakumar, K., Nobashi, T., & Rubin, D. L. CT-ORG: a dataset of CT volumes with multiple organ segmentations. The Cancer Imaging Archive (TCIA) https:\/\/doi.org\/10.7937\/tcia.2019.tt7f4v7o (2019).","DOI":"10.7937\/tcia.2019.tt7f4v7o"},{"key":"1238_CR32","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1002\/path.6030","volume":"259","author":"T Bekkhus","year":"2023","unstructured":"Bekkhus, T., Olofsson, A., Sun, Y., Magnusson, P. U. & Ulvmar, M. H. Stromal transdifferentiation drives lipomatosis and induces extensive vascular remodeling in the aging human lymph node. J. Pathol. 259, 236\u2013253 (2023).","journal-title":"J. Pathol."},{"key":"1238_CR33","doi-asserted-by":"publisher","first-page":"2860","DOI":"10.1182\/blood.V95.9.2860.009k35_2860_2868","volume":"95","author":"FF Fagnoni","year":"2000","unstructured":"Fagnoni, F. F. et al. Shortage of circulating naive CD8+ T cells provides new insights on immunodeficiency in aging. Blood 95, 2860\u20132868 (2000).","journal-title":"Blood"},{"key":"1238_CR34","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1111\/acel.12384","volume":"15","author":"O Brice\u00f1o","year":"2016","unstructured":"Brice\u00f1o, O. et al. Reduced na\u00efve CD8+ T-cell priming efficacy in elderly adults. Aging Cell 15, 14\u201321 (2016).","journal-title":"Aging Cell"},{"key":"1238_CR35","doi-asserted-by":"publisher","first-page":"2836","DOI":"10.1016\/j.immuni.2023.10.013","volume":"56","author":"M Terekhova","year":"2023","unstructured":"Terekhova, M. et al. Single-cell atlas of healthy human blood unveils age-related loss of NKG2C+GZMB\u2212CD8+ memory T cells and accumulation of type 2 memory T cells. Immunity 56, 2836\u20132854 (2023).","journal-title":"Immunity"},{"key":"1238_CR36","doi-asserted-by":"publisher","first-page":"2362","DOI":"10.1016\/j.immuni.2024.08.019","volume":"57","author":"P Bohacova","year":"2024","unstructured":"Bohacova, P. et al. Multidimensional profiling of human T cells reveals high CD38 expression, marking recent thymic emigrants and age-related naive T cell remodeling. Immunity 57, 2362\u20132379 (2024).","journal-title":"Immunity"},{"key":"1238_CR37","doi-asserted-by":"publisher","first-page":"e3000383","DOI":"10.1371\/journal.pbio.3000383","volume":"17","author":"JE Mold","year":"2019","unstructured":"Mold, J. E. et al. Cell generation dynamics underlying naive T-cell homeostasis in adult humans. PLoS Biol. 17, e3000383 (2019).","journal-title":"PLoS Biol."},{"key":"1238_CR38","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1073\/pnas.1525167113","volume":"113","author":"KM Quinn","year":"2016","unstructured":"Quinn, K. M. et al. Heightened self-reactivity associated with selective survival, but not expansion, of naive virus-specific CD8+ T cells in aged mice. Proc. Natl Acad. Sci. USA 113, 1333\u20131338 (2016).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1238_CR39","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1111\/j.1365-2567.2004.02006.x","volume":"114","author":"L Lazuardi","year":"2005","unstructured":"Lazuardi, L. et al. Age-related loss of na\u00efve T cells and dysregulation of T-cell\/B-cell interactions in human lymph nodes. Immunology 114, 37\u201343 (2005).","journal-title":"Immunology"},{"key":"1238_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11291","volume":"7","author":"JT White","year":"2016","unstructured":"White, J. T. et al. Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner. Nat. Commun. 7, 11291 (2016).","journal-title":"Nat. Commun."},{"key":"1238_CR41","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1038\/nri.2017.34","volume":"17","author":"JT White","year":"2017","unstructured":"White, J. T., Cross, E. W. & Kedl, R. M. Antigen-inexperienced memory CD8+ T cells: where they come from and why we need them. Nat. Rev. Immunol. 17, 391\u2013400 (2017).","journal-title":"Nat. Rev. Immunol."},{"key":"1238_CR42","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201798518","volume":"37","author":"A Drobek","year":"2018","unstructured":"Drobek, A. et al. Strong homeostatic TCR signals induce formation of self-tolerant virtual memory CD8+ T cells. EMBO J. 37, e98518 (2018).","journal-title":"EMBO J."},{"key":"1238_CR43","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1038\/s41577-019-0180-1","volume":"19","author":"JJ Goronzy","year":"2019","unstructured":"Goronzy, J. J. & Weyand, C. M. Mechanisms underlying T cell ageing. Nat. Rev. Immunol. 19, 573\u2013583 (2019).","journal-title":"Nat. Rev. Immunol."},{"key":"1238_CR44","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1038\/ni.3483","volume":"17","author":"V Pulko","year":"2016","unstructured":"Pulko, V. et al. Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses. Nat. Immunol. 17, 966\u2013975 (2016).","journal-title":"Nat. Immunol."},{"key":"1238_CR45","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1084\/jem.193.10.1179","volume":"193","author":"P Wong","year":"2001","unstructured":"Wong, P., Barton, G. M., Forbush, K. A. & Rudensky, A. Y. Dynamic tuning of T cell reactivity by self-peptide\u2013major histocompatibility complex ligands. J. Exp. Med. 193, 1179\u20131187 (2001).","journal-title":"J. Exp. Med."},{"key":"1238_CR46","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay3224","volume":"367","author":"J-E Park","year":"2020","unstructured":"Park, J.-E. et al. A cell atlas of human thymic development defines T cell repertoire formation. Science 367, eaay3224 (2020).","journal-title":"Science"},{"key":"1238_CR47","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.ade0182","volume":"7","author":"M Cordes","year":"2022","unstructured":"Cordes, M. et al. Single-cell immune profiling reveals thymus-seeding populations, T cell commitment, and multilineage development in the human thymus. Sci. Immunol. 7, eade0182 (2022).","journal-title":"Sci. Immunol."},{"key":"1238_CR48","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abg9433","volume":"6","author":"S Hou","year":"2021","unstructured":"Hou, S. et al. Virtual memory T cells orchestrate extralymphoid responses conducive to resident memory. Sci. Immunol. 6, eabg9433 (2021).","journal-title":"Sci. Immunol."},{"key":"1238_CR49","doi-asserted-by":"publisher","first-page":"297","DOI":"10.4049\/jimmunol.2200316","volume":"210","author":"T Hussain","year":"2023","unstructured":"Hussain, T. et al. Helminth infection-induced increase in virtual memory CD8+ T cells is transient, driven by IL-15, and absent in aged mice. J. Immunol. 210, 297\u2013309 (2023).","journal-title":"J. Immunol."},{"key":"1238_CR50","doi-asserted-by":"publisher","first-page":"2516","DOI":"10.4049\/jimmunol.1102213","volume":"188","author":"AD Akue","year":"2012","unstructured":"Akue, A. D., Lee, J.-Y. & Jameson, S. C. Derivation and maintenance of virtual memory CD8+ T cells. J. Immunol. 188, 2516\u20132523 (2012).","journal-title":"J. Immunol."},{"key":"1238_CR51","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/S1074-7613(02)00508-3","volume":"18","author":"B Min","year":"2003","unstructured":"Min, B. et al. Neonates support lymphopenia-induced proliferation. Immunity 18, 131\u2013140 (2003).","journal-title":"Immunity"},{"key":"1238_CR52","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1111\/joim.12384","volume":"278","author":"G Bergstr\u00f6m","year":"2015","unstructured":"Bergstr\u00f6m, G. et al. The Swedish CArdioPulmonary BioImage Study: objectives and design. J. Intern. Med. 278, 645\u2013659 (2015).","journal-title":"J. Intern. Med."},{"key":"1238_CR53","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1097\/RTI.0000000000000349","volume":"33","author":"MJ Drabkin","year":"2018","unstructured":"Drabkin, M. J. et al. Age-stratified patterns of thymic involution on multidetector CT. J. Thorac. Imaging 33, 409\u2013416 (2018).","journal-title":"J. Thorac. Imaging"},{"key":"1238_CR54","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s12979-023-00371-7","volume":"20","author":"M Sandstedt","year":"2023","unstructured":"Sandstedt, M. et al. Complete fatty degeneration of thymus associates with male sex, obesity and loss of circulating naive CD8+ T cells in a Swedish middle-aged population. Immun. Ageing 20, 45 (2023).","journal-title":"Immun. Ageing"},{"key":"1238_CR55","doi-asserted-by":"publisher","first-page":"7282","DOI":"10.4049\/jimmunol.172.12.7282","volume":"172","author":"TL Staton","year":"2004","unstructured":"Staton, T. L., Johnston, B., Butcher, E. C. & Campbell, D. J. Murine CD8+ recent thymic emigrants are \u03b1E integrin-positive and CC chemokine ligand 25 responsive. J. Immunol. 172, 7282\u20137288 (2004).","journal-title":"J. Immunol."},{"key":"1238_CR56","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.cell.2018.05.029","volume":"174","author":"NL Smith","year":"2018","unstructured":"Smith, N. L. et al. Developmental origin governs CD8+ T cell fate decisions during infection. Cell 174, 117\u2013130 (2018).","journal-title":"Cell"},{"key":"1238_CR57","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/s41586-024-07789-z","volume":"633","author":"T Lakshmikanth","year":"2024","unstructured":"Lakshmikanth, T. et al. Immune system adaptation during gender-affirming testosterone treatment. Nature 633, 155\u2013164 (2024).","journal-title":"Nature"},{"key":"1238_CR58","doi-asserted-by":"publisher","first-page":"2741","DOI":"10.4049\/jimmunol.175.4.2741","volume":"175","author":"JS Sutherland","year":"2005","unstructured":"Sutherland, J. S. et al. Activation of thymic regeneration in mice and humans following androgen blockade. J. Immunol. 175, 2741\u20132753 (2005).","journal-title":"J. Immunol."},{"key":"1238_CR59","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1158\/1078-0432.CCR-07-1784","volume":"14","author":"JS Sutherland","year":"2008","unstructured":"Sutherland, J. S. et al. Enhanced immune system regeneration in humans following allogeneic or autologous hemopoietic stem cell transplantation by temporary sex steroid blockade. Clin. Cancer Res. 14, 1138\u20131149 (2008).","journal-title":"Clin. Cancer Res."},{"key":"1238_CR60","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1158\/1078-0432.CCR-22-2812","volume":"29","author":"C Robert","year":"2023","unstructured":"Robert, C. et al. Phase I study of androgen deprivation therapy in combination with anti\u2013PD-1 in melanoma patients pretreated with anti\u2013PD-1. Clin. Cancer Res. 29, 858\u2013865 (2023).","journal-title":"Clin. Cancer Res."},{"key":"1238_CR61","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.humimm.2010.02.007","volume":"71","author":"MD Morse","year":"2010","unstructured":"Morse, M. D. & McNeel, D. G. Prostate cancer patients treated with androgen deprivation therapy develop persistent changes in adaptive immune responses. Hum. Immunol. 71, 496\u2013504 (2010).","journal-title":"Hum. Immunol."},{"key":"1238_CR62","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12865","volume":"18","author":"HL Thompson","year":"2019","unstructured":"Thompson, H. L. et al. Lymph nodes as barriers to T-cell rejuvenation in aging mice and nonhuman primates. Aging Cell 18, e12865 (2019).","journal-title":"Aging Cell"},{"key":"1238_CR63","doi-asserted-by":"publisher","first-page":"e42677","DOI":"10.1371\/journal.pone.0042677","volume":"7","author":"TSP Heng","year":"2012","unstructured":"Heng, T. S. P. et al. Impact of sex steroid ablation on viral, tumour and vaccine responses in aged mice. PLOS ONE 7, e42677 (2012).","journal-title":"PLOS ONE"},{"key":"1238_CR64","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1038\/s41586-026-10243-x","volume":"652","author":"S Bernatz","year":"2026","unstructured":"Bernatz, S. et al. Thymic health and immunotherapy outcomes in patients with cancer. Nature 652, 995\u20131003 https:\/\/doi.org\/10.1038\/s41586-026-10243-x (2026).","journal-title":"Nature"},{"key":"1238_CR65","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/j.coi.2011.05.005","volume":"23","author":"MA Blackman","year":"2011","unstructured":"Blackman, M. A. & Woodland, D. L. The narrowing of the CD8+ T cell repertoire in old age. Curr. Opin. Immunol. 23, 537\u2013542 (2011).","journal-title":"Curr. Opin. Immunol."},{"key":"1238_CR66","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aah6506","volume":"1","author":"JJC Thome","year":"2016","unstructured":"Thome, J. J. C. et al. Long-term maintenance of human naive T cells through in situ homeostasis in lymphoid tissue sites. Sci. Immunol. 1, eaah6506 (2016).","journal-title":"Sci. Immunol."},{"key":"1238_CR67","doi-asserted-by":"publisher","first-page":"3333","DOI":"10.1016\/j.cell.2023.06.020","volume":"186","author":"G Dolton","year":"2023","unstructured":"Dolton, G. et al. Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy. Cell 186, 3333\u20133349 (2023).","journal-title":"Cell"},{"key":"1238_CR68","doi-asserted-by":"publisher","first-page":"1662","DOI":"10.1016\/j.ccell.2023.08.001","volume":"41","author":"G Escobar","year":"2023","unstructured":"Escobar, G. et al. Tumor immunogenicity dictates reliance on TCF1 in CD8+ T cells for response to immunotherapy. Cancer Cell 41, 1662\u20131679 (2023).","journal-title":"Cancer Cell"},{"key":"1238_CR69","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.immuni.2007.07.007","volume":"27","author":"JJ Moon","year":"2007","unstructured":"Moon, J. J. et al. Naive CD4+ T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 27, 203\u2013213 (2007).","journal-title":"Immunity"},{"key":"1238_CR70","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1038\/s41586-024-07238-x","volume":"628","author":"JB Ross","year":"2024","unstructured":"Ross, J. B. et al. Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity. Nature 628, 162\u2013170 (2024).","journal-title":"Nature"},{"key":"1238_CR71","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1093\/gerona\/glz029","volume":"74","author":"AR Masters","year":"2019","unstructured":"Masters, A. R. et al. Assessment of lymph node stromal cells as an underlying factor in age-related immune impairment. J. Gerontol. A 74, 1734\u20131743 (2019).","journal-title":"J. Gerontol. A"},{"key":"1238_CR72","doi-asserted-by":"publisher","first-page":"1593","DOI":"10.1038\/s41590-024-01915-9","volume":"25","author":"AI Kousa","year":"2024","unstructured":"Kousa, A. I. et al. Age-related epithelial defects limit thymic function and regeneration. Nat. Immunol. 25, 1593\u20131606 (2024).","journal-title":"Nat. Immunol."},{"key":"1238_CR73","doi-asserted-by":"publisher","unstructured":"Menzel, L. et al. Distant lymph nodes compensate for resected tumor-draining lymph nodes during cancer immunotherapy. Preprint at bioRxiv https:\/\/doi.org\/10.1101\/2023.09.19.558262 (2025).","DOI":"10.1101\/2023.09.19.558262"},{"key":"1238_CR74","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1159\/000348677","volume":"7","author":"L McFarlane","year":"2013","unstructured":"McFarlane, L., Truong, V., Palmer, J. S. & Wilhelm, D. Novel PCR assay for determining the genetic sex of mice. Sex. Dev. 7, 207\u2013211 (2013).","journal-title":"Sex. Dev."},{"key":"1238_CR75","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl5197","volume":"376","author":"C Dom\u00ednguez Conde","year":"2022","unstructured":"Dom\u00ednguez Conde, C. et al. Cross-tissue immune cell analysis reveals tissue-specific features in humans. Science 376, eabl5197 (2022).","journal-title":"Science"},{"key":"1238_CR76","doi-asserted-by":"publisher","first-page":"47","DOI":"10.12688\/f1000research.22139.1","volume":"9","author":"N Borcherding","year":"2020","unstructured":"Borcherding, N., Bormann, N. L. & Kraus, G. scRepertoire: an R-based toolkit for single-cell immune receptor analysis. F1000Res 9, 47 (2020).","journal-title":"F1000Res"},{"key":"1238_CR77","doi-asserted-by":"publisher","unstructured":"Park, J.-E., Teichmann, S., Haniffa, M. & Taghon, T. Collection of codes and annotated matrix for the paper \u201cA cell atlas of human thymic development defines T cell repertoire formation.\u201d Zenodo https:\/\/doi.org\/10.5281\/zenodo.3711134 (2020).","DOI":"10.5281\/zenodo.3711134"}],"container-title":["Nature Aging"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s43587-026-01238-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43587-026-01238-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43587-026-01238-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T06:07:16Z","timestamp":1791958036000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s43587-026-01238-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,9]]},"references-count":77,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["1238"],"URL":"https:\/\/doi.org\/10.1038\/s43587-026-01238-4","relation":{},"ISSN":["2662-8465"],"issn-type":[{"value":"2662-8465","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,9]]},"assertion":[{"value":"15 January 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 October 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"H.Z. is now employed by Arnatar Therapeutics; his affiliation with Arnatar began after completion of the work presented here, and there is no connection between Arnatar and the present study. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}