Dysregulated thymus-ovary axis promotes virtual memory T cell polarization to aggravate PMOS pathology

Polyendocrine metabolic ovarian syndrome (PMOS) is traditionally attributed to dysfunction of the hypothalamic-pituitary-gonadal axis, but the contribution of extra-reproductive organs remains unclear. Here, we identify a thymus-ovary pathway linking androgen excess to ovarian inflammation. Androgen receptor signaling in thymic stromal cells induces early thymic involution and impairs thymic output before overt reproductive pathology emerges. Athymic mice and Rag1^-/- mice with preserved thymic stroma are comparably resistant to PMOS-like pathology, supporting an essential role for thymus-derived T cells in disease development. Antibody-mediated depletion further reveals CD8⁺, but not CD4⁺, T cells are required for disease manifestation. Among CD8⁺ T-cell subsets, virtual memory CD8⁺ T (T_VM) cells preferentially expand in patients and experimental models and accumulate in reproductive tissues. These cells exacerbate disease severity and prolong pathology after androgen withdrawal. Mechanistically, ovarian T_VM cells secrete pro-inflammatory cytokines and CCL5, thereby recruiting myeloid cells to the ovary and amplifying local inflammation. Therapeutically, JAK inhibition restricts T_VM-cell differentiation, redirects CD8⁺ T-cell fate away from a cytotoxic CXCR3^high state and ameliorates PMOS-like pathology. These findings identify T_VM cells as key effectors linking androgen-induced thymic remodeling to ovarian inflammation and persistent pathology.