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) -gamma and tumor necrosis factor (TNF) -alpha 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.

Automated summary

This study revealed an augmented T helper 1 (T(H)1) response and regulatory T (T-reg) cell deficiency in patients with premature ovarian insufficiency (POI), which was strongly correlated with disease severity. In mouse models, increased infiltration of T(H)1 cells in the ovary led to follicle atresia and ovarian insufficiency, while T-reg cells were able to prevent and reverse these effects. Furthermore, interferon (IFN) -gamma and tumor necrosis factor (TNF) -alpha were found to cooperate in promoting granulosa cell apoptosis and suppressing steroidogenesis in the context of POI.