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Here, we uncover a sex-biased mechanism of immune aging in which an early, male-biased depletion of naive CD8 T cells driven by accelerated, antigen-agnostic differentiation into virtual memory cells is combined with age-related thymic involution that limits naive CD8 T cell replenishment. These mechanisms lead to contraction of lymph nodes and reduced local naive T cell clone availability, limiting cancer antigen recognition capacity. Therapeutic thymus regeneration via androgen ablation repopulates naive CD8 T cells in lymph nodes, which reinvigorates cancer-specific T cell responses and enhances responsiveness to immune checkpoint blockade. These findings reveal the crucial impact of sex and age on naive T cell clone abundance in lymph nodes and suggest strategies to restore immune competence in middle-aged males.<\/jats:p>","DOI":"10.1101\/2025.02.11.637693","type":"posted-content","created":{"date-parts":[[2025,2,16]],"date-time":"2025-02-16T02:45:24Z","timestamp":1739673924000},"source":"Crossref","is-referenced-by-count":1,"title":["Lymph node contraction links sex-biased naive CD8 T cell decline to compromised antigen recognition during middle age"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3816-6255","authenticated-orcid":false,"given":"Lutz","family":"Menzel","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, USA"},{"name":"Immunology of Aging, Leibniz Institute on Aging - Fritz Lipmann Institute e.V. 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