Toxoplasma gondii excreted‐secreted antigens suppress Foxp3 via PI3K‐AKT‐mTOR signaling pathway

: Toxoplasma gondii excreted-secreted antigens (ESA) cause spontaneous abortion or fetal teratogenesis during the pregnancy in mice, especially in the early stage. Those adverse pregnancy outcomes are due to the deficit in regulatory T cells (Tregs). Forkhead box P3 (Foxp3), a critical transcription factor, modulates Tregs differentiation and its function. Besides, phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) signaling network is implicated in interfering with Foxp3 induction. We previously demonstrated that ESA diminished the number of Tregs and inhibited its function. And ESA suppressed Foxp3 expression via the attenuation of transforming growth factor β RII/Smad2/Smad3/Smad4 pathway. The current study aimed to investigate whether the PI3K-AKT-mTOR signaling network is involved in Foxp3 downregulation induced by ESA. We found that ESA upregulated PI3K, P-AKT, mTOR, and P-mTOR. Knockdown of PI3K cooperated with ESA to restore Foxp3 expression mediated by ESA. This suppressive role of ESA on Foxp3 expression was abrogated by AKT inhibitor. In addition, neutralization of Toll-like receptor 4 could restore the expression of Foxp3, PI3K, and its downstream effectors induced by ESA. Collectively, the findings indicated that ESA inhibited Foxp3 expression via the upregulation of PI3K-AKT-mTOR signaling pathway.