Abstract
Vertical transmission of Toxoplasma gondii (T. gondii) infection during gestation can result in severe complications such as abortion, congenital malformation, fetal teratogenesis, etc. Immune inhibitory molecule Tim-3 was discovered to be expressed on some decidual immune cells and participates in the maintenance of maternal-fetal tolerance. Dysregulation of Tim-3 expression on decidual NK (dNK) cells was observed in several cases of pregnancy complications, whereas the role of Tim-3 on dNK cells during T. gondii infection remains unclear. In the present study, T. gondii infected Tim-3-/- pregnant mice, and anti-Tim-3 neutralizing antibody treated and infected human dNK cells were successfully established to explore the role of Tim-3 in dysfunction of dNK cells during abnormal pregnancy. Our results illustrated that Tim-3-/- pregnant mice displayed more worse pregnancy outcomes with T. gondii infection compared to infected WT pregnant mice. Also, it demonstrated that Tim-3 expression on dNK cells was significantly down-regulated following T. gondii infection. Data suggested a remarkable activation of dNK cells in Tim-3-/- mice and anti-Tim-3 neutralizing antibody treated and infected groups, with higher ratios of activating receptor NKG2D to inhibitory receptor NKG2A or KIR2DL4, IFN-γ/IL-10, and increased granule production compared with that of the infected group. Mechanism analysis proved that T. gondii-induced Tim-3 down-regulation significantly activated the phosphatidylinositol-3-kinase (PI3K)-AKT and JAK-STAT signaling pathway, by which the GranzymeB, Perforin, IFN-γ, and IL-10 production were further up-regulated. Our research demonstrated that the decrease of Tim-3 on dNK cells caused by T. gondii infection further led to dNK cells function disorder, which finally contributed to the development of abnormal pregnancy outcomes.
Highlights
Toxoplasma gondii (T. gondii) is an obligate intracellular parasite which is capable of infecting all species of warm-blooded animals via the ingestion of tissue cysts or sporulated oocysts (RobertGangneux and Dardé, 2012)
We observed abnormal pregnancy outcomes caused by T. gondii infection, with erected fur, spiritual malaise, and inflammatory hyperemia of placentas in infected mice compared with the uninfected group (Figures 1A, B)
Our previous studies have reported that the dysfunctions of decidual immune cells such as decidual NK (dNK) cells, macrophages, Tregs, and DCs in response to T. gondii infection result in abnormal pregnancy outcomes (Zhang et al, 2012a; Li et al, 2017b; Xu et al, 2017)
Summary
Toxoplasma gondii (T. gondii) is an obligate intracellular parasite which is capable of infecting all species of warm-blooded animals via the ingestion of tissue cysts or sporulated oocysts (RobertGangneux and Dardé, 2012). The dNK cells modulate maternal-fetal tolerance by maintaining stable functional molecule expression (NKG2A and KIR2DL4) and cytokines production (Rouas-Freiss et al, 1997; Fu et al, 2017). The interaction between dNK inhibitory receptors (KIR2DL4, ILT-2) and their ligand HLA-G on invading trophoblasts allows the extensive remodeling of the maternal vasculature during the early weeks of pregnancy and inhibits the killing activity of NK cells to HLA-G positive trophoblasts (Yan et al, 2007; Ferreira et al, 2017). Our previous studies have reported an excessive activation of dNK cells after T. gondii infection with imbalance between inhibitory receptors (NKG2A, KIR2DL4) and activating receptors NKG2D (Liu et al, 2013; Xu et al, 2013; Liu et al, 2014). The detailed mechanism of dNK cells dysfunction in T. gondii infection remains unknown and requires further study
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