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bioRxiv · 10.1101/2025.02.11.637693

Lymph nodes link sex-biased immune aging to compromised antigen recognition

Menzel, L.·Zschummel, M.·O'Melia, M. J.·Zhou, H.·Lei, P.-J.·Liu, L.·Sen, D. R.·Munn, L. L.·Padera, T. P.
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Abstract

The numerical abundance of diverse naive CD8 T cell clones is essential to provide broad protection against infection and cancer. 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.

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Menzel, L., Zschummel, M., O'Melia, M. J., Zhou, H., Lei, P.-J., Liu, L., Sen, D. R., Munn, L. L., Padera, T. P.. 2025-02-15. Lymph nodes link sex-biased immune aging to compromised antigen recognition. https://doi.org/10.1101/2025.02.11.637693

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