Polycystic ovary syndrome (PCOS) is a complex condition with clear genetic susceptibilities that impact the heterogeneous clinical presentation of symptoms and severity through unknown mechanisms. Chronic inflammation is linked to PCOS, but a clear cause-and-effect relationship has yet to be established. This study used an in depth systems immunology approach and a letrozole-induced PCOS mouse model to identify changes in inflammatory factors associated with PCOS symptoms. By analyzing immune cells and secreted cytokines from 22 different mouse strains, we identified TNF-β as a key T cell-derived cytokine associated with PCOS, regardless of genetic background. We confirmed elevated TNF-β transcripts in immune cells from women with PCOS. Importantly, we used a knockout of TCRα to show that functional T cells are a necessary component of driving PCOS features in letrozole-treated female mice. These findings implicate T cells and specifically TNF-β production in the development of PCOS impairments. T cells are therefore an attractive target for the future development of anti-inflammatory therapeutics to improve PCOS symptoms.