Search

Myeloid-derived suppressor cells (MDSCs) play a key role in maintaining maternal-fetal tolerance for a successful pregnancy, but the role of MDSCs in abnormal pregnancy caused by Toxoplasma gondii infection is unknown. Herein, we revealed a distinct mechanism by which T-cell immunoglobulin domain and mucin domain containing protein-3 (Tim-3), an immune checkpoint receptor that balances maternal-fetal tolerance during pregnancy, contributes to the immunosuppressive function of MDSCs during T. gondii infection. The expression of Tim-3 in decidual MDSCs was significantly downregulated following T. gondii infection. The proportion of monocytic MDSCs population, the inhibitory effect of MDSCs on T-cell proliferation, the levels of STAT3 phosphorylation, and the expression of functional molecules (Arg-1 and IL-10) in MDSCs were all decreased in T. gondii-infected pregnant Tim-3 gene knockout (Tim-3KO) mice compared with infected pregnant WT mice. After treatment with Tim-3-neutralizing Ab in vitro, the expression levels of Arg-1, IL-10, C/EBPβ, and p-STAT3 were decreased, the interaction between Fyn and Tim-3 or between Fyn and STAT3 was weakened, and the binding ability of C/EBPβ to the promoters of ARG1 and IL10 was decreased in human decidual MDSCs with T. gondii infection, while opposite results were observed following treatment with galectin-9 (a ligand for Tim-3). Inhibitors of Fyn and STAT3 also downregulated the expression of Arg-1 and IL-10 in decidual MDSCs and exacerbated adverse pregnancy outcomes caused by T. gondii infection in mice. Therefore, our studies discovered that the decrease of Tim-3 after T. gondii infection could downregulate the functional molecules of Arg-1 and IL-10 expression in decidual MDSCs through the Fyn-STAT3-C/EBPβ signaling pathway and weaken their immunosuppressive function, which eventually contribute to the development of adverse pregnancy outcomes. Author summary: Pregnant women in their first trimester with a primary infection of T. gondii are particularly susceptible resulting in a number of serious adverse pregnancy outcomes. Previous studies have shown that T. gondii infection results in the dysfunction of immune cell function at the maternal-fetal interface, which destroys the function of maternal-fetal immune tolerance for a successful pregnancy. MDSCs have an immunosuppressive capacity and play an important role in the maintenance of normal pregnancy. However, the role of MDSCs in the adverse pregnancy outcomes caused by T. gondii infection remains unknown. Here, we analyzed the effect of an immunosuppressive molecule Tim-3 on the function of decidual MDSCs following T. gondii infection. Our results showed that T. gondii infection downregulated the proportion of monocytic MDSCs population, the inhibitory ability of MDSCs on T cell proliferation, the level of STAT3 phosphorylation, and the expression of functional molecules (Arg-1 and IL-10) in MDSCs from the pregnant Tim-3KO mice compared with the pregnant WT mice. Further study showed that the decrease of Tim-3 expression caused by T. gondii infection could downregulate Arg-1 and IL-10 expression in decidual MDSCs via the Fyn-STAT3-C/EBPβ signaling pathway and weaken their immunosuppressive function. This work suggested that MDSCs dysfunction resulting from the downregulation of Tim-3 after T. gondii infection may be an important mechanism of adverse pregnancy outcomes, which may provide theoretical information for prophylactic and/or therapeutic treatments against the infection-related abnormal pregnancy. [ABSTRACT FROM AUTHOR]