Treg deficiency‐mediated TH1 response causes human premature ovarian insufficiency through apoptosis and steroidogenesis dysfunction of granulosa cells

Immune dysregulation has long been proposed as a component of premature ovarian insufficiency (POI), but the underlying mediators and mechanisms remain largely unknown. Here we showed that patients with POI had augmented T helper 1 (T_H 1) responses and regulatory T (T_reg ) cell deficiency in both the periphery and the ovary compared to the control women. The increased ratio of T_H 1:T_reg cells was strongly correlated with the severity of POI. In mouse models of POI, the increased infiltration of T_H 1 cells in the ovary resulted in follicle atresia and ovarian insufficiency, which could be prevented and reversed by T_reg cells. Importantly, interferon (IFN) -γ and tumor necrosis factor (TNF) -α cooperatively promoted the apoptosis of granulosa cells and suppressed their steroidogenesis by modulating CTGF and CYP19A1. We have thus revealed a previously unrecognized T_reg cell deficiency-mediated T_H 1 response in the pathogenesis of POI, which should have implications for therapeutic interventions in patients with POI.