Toxoplasma gondii Infection of Decidual CD1c+ Dendritic Cells Enhances Cytotoxicity of Decidual Natural Killer Cells

Abstract

There is crosstalk between decidual natural killer (dNK) cells and decidual dendritic cells (dDCs) that promotes tolerance of trophoblast cells carrying paternally derived antigens. In the present study, we report that infection of CD1c(+) dDCs with Toxoplasma gondii enhanced gamma interferon (IFN-γ) production by dNK cells in co-culture. The enhancement of IFN-γ production was induced by cytokine IL-12 which increased obviously in co-culture of dDCs with dNK cells following T. gondii infection, and this enhancement largely abrogated when cells were cultured in the presence of an anti-IL-12 antibody. The expression of KIR2DL4 and NKG2D on dNK cells was increased after T. gondii infection, and higher expression of NKG2D was induced by co-cultured dDCs. Neutralization of IL-12 decreased NKG2D expression on dNK cells. Furthermore, dDCs with T. gondii infection increased the cytotoxicity of co-cultured dNK cells against K562 target cells, which was mediated by activating receptor of NKG2D. Thus, T. gondii infection of dDCs enhanced dNK cell IFN-γ production and NKG2D expression, and then led to increased cytotoxicity of dNK cells. The up-regulated dNK cell cytotoxicity at the maternal-fetal interface may contribute to abnormal pregnancy outcomes caused by T. gondii infection in early pregnancy.

How does toxoplasmosis affect the maternal‐foetal immune interface and pregnancy?

“…However, in other infection models, such as for Trypanosoma cruzi , inhibition of implantation and cell division has also been described . Nevertheless, T. gondii acute infection induces transient changes in systemic expression of many immune mediators, which in theory have the potential to antagonize normal immune changes during pregnancy (Figure ) …”

“…Toxoplasma gondii infection can have profound effects on the systemic maternal cellular immune responses and affects normal immune mechanisms at the maternal‐foetal interface and can thus influence pregnancy outcome . T. gondii strains with different virulence are known to infect decidual immune cell populations and the placenta, a prime anatomical location to alter immune responses at the maternal‐foetal interface . On the other hand, the immunomodulation during pregnancy may contribute to the development of an environment (dominated by Th2 and Treg cells) that facilitates the escape of T. gondii from the immune response, leading to increased maternal pathology or an increased likelihood of congenital transmission …”

“…dNK cells also secrete a variety of cytokines, such as TNF‐α, TNF‐β, IL‐10, IL‐13 and GM‐CSF . These immune cells are the main source of IFN‐γ, which are essential for implantation and early placental progression . In recent years, several studies have demonstrated the ability of T. gondii to modify the immune profile of decidual cells and to invade and multiply within uterine dNK cells .…”

“…However, contrary to these observations during bacterial infections, in vitro studies have shown that T. gondii ‐infected human dDCs produced IL‐12 which increased the cytotoxicity of dNK cells as determined by increased expression of NKG2D and production of IFN‐γ. The presence of increased IL‐12 and IFN‐γ levels would favour Th1 cells and suppress Th2 cells and thus contribute to disruption of pregnancy …”

The Effect of TGF-β on Treg Cells in Adverse Pregnancy Outcome upon Toxoplasma gondii Infection

“…Our previous studies have shown that the abnormal pregnancy outcomes caused by T. gondii infection are associated with an abnormal immuno-microenvironment, which contains immunocytes and cytokines, at the maternal–fetal interface (Zhang H. et al, 2012; Xu et al, 2013; Liu X. et al, 2014; Liu Y. et al, 2014). We previously reported that the placental TGF-β level was decreased in mice with adverse pregnancy outcomes after T. gondii infection (Zhang H. et al, 2012; Liu Y. et al, 2014).…”