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

The abundance of diverse naive CD8+ 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+ T cells driven by accelerated, antigen-agnostic differentiation into virtual memory cells combines with thymic involution, limiting naive CD8+ 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+ 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.