Human Cytomegalovirus Infection Elicits New Decidual Natural Killer Cell Effector Functions

Abstract

During the first trimester of pregnancy the uterus is massively infiltrated by decidual natural killer cells (dNK). These cells are not killers, but they rather provide a microenvironment that is propitious to healthy placentation. Human cytomegalovirus (HCMV) is the most common cause of intrauterine viral infections and a known cause of severe birth defects or fetal death. The rate of HCMV congenital infection is often low in the first trimester of pregnancy. The mechanisms controlling HCMV spreading during pregnancy are not yet fully revealed, but evidence indicating that the innate immune system plays a role in controlling HCMV infection in healthy adults exists. In this study, we investigated whether dNK cells could be involved in controlling viral spreading and in protecting the fetus against congenital HCMV infection. We found that freshly isolated dNK cells acquire major functional and phenotypic changes when they are exposed to HCMV-infected decidual autologous fibroblasts. Functional studies revealed that dNK cells, which are mainly cytokines and chemokines producers during normal pregnancy, become cytotoxic effectors upon their exposure to HCMV-infected autologous decidual fibroblasts. Both the NKG2D and the CD94/NKG2C or 2E activating receptors are involved in the acquired cytotoxic function. Moreover, we demonstrate that CD56pos dNK cells are able to infiltrate HCMV-infected trophoblast organ culture ex-vivo and to co-localize with infected cells in situ in HCMV-infected placenta. Taken together, our results present the first evidence suggesting the involvement of dNK cells in controlling HCMV intrauterine infection and provide insights into the mechanisms through which these cells may operate to limit the spreading of viral infection to fetal tissues.

The HLA-G cycle provides for both NK tolerance and immunity at the maternal–fetal interface

“…In the absence of IL-15, after 10 h of coincubation, dNK failed to respond to HCMV-infected DSC but degranulated at a low level in the presence of IL-15 (Fig. 5A), similar to that observed previously (29). However, after preincubation of dNK with IL-15 for 18 h no lag in degranulation was observed, and after 10 h of coincubation 18% of dNK degranulated, half of which was specific to HCMV infection (Fig.…”

“…The control of virus infection at the interface by dNK may require interruption of the HLA-G cycle, which could include inhibition either of reacquisition or endocytosis of HLA-G and is illustrated in the case of HCMV infection. No cytotoxicity after coculture of dNK with HCMVinfected DSC for 4 h was observed but, after 6-18 h of contact, dNK were fully able to kill the HCMV-infected DSC (29). In addition, in the present experiment, dNK were fully able to degranulate in response to HCMV-infected DSC without a lag and within 10 h of culture with IL-15, whereas in the absence of IL-15, dNK did not degranulate in response to HCMV-infected DSC.…”

“…The inhibition of dNK cytotoxicity that results is clearly an important facet of maternal-fetal tolerance. However, it raises the problem of how the pregnant female is able to respond to events that require participation of cytotoxic dNK, for example during a placental HCMV infection, a common viral infection at this site (29,31). One possibility could be that the HLA-G cycle between EVT and dNK provides direct inhibition of cytotoxicity at an individual EVT-NK synapse as well as a prolonged but temporary inhibition of the dNK cytolytic machinery during HLA-G endocytosis and endolysosomal signaling events.…”

“…A recent study demonstrated that dNK can kill human cytomegalo virus (HCMV)-infected decidual stromal cells (DSC) upon coincubation, but only after a lag of 6 h or longer (29). Here, fresh dNK were cocultured with DSC and HCMV-infected DSC in the presence or absence of IL-15.…”

HLA-G-mediated NK cell senescence promotes vascular remodeling: implications for reproduction

“…11 Coculture of human cytomegalovirus-infected decidual fibroblasts with decidual NK cells from early gestation resulted in significant induction of an array of cytokines and chemokines, such as vascular endothelial growth factor-A, IL-6, chemokine (C-X-C motif) ligand 1 and macrophage chemoattractant protein (MCP)-1. 12 A combination of the modulation of expression of NK receptors and pathogen-induced ligands allows NK cells to overcome the inhibition of decidual NK killing seen in normal pregnancy. There are regulatory mechanisms in place to prevent killing at the maternal/fetal interface during a healthy pregnancy.…”