Lymph node contraction links sex-biased naive CD8 T cell decline to compromised antigen recognition during middle age

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.