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 CD56 ^pos 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.

Author Summary

Human cytomegalovirus (HCMV) is a herpes virus that can establish persisting infection in immunocompetent hosts. HCMV primary infection during pregnancy is devastating; it can result in up to 75% of congenital infections and it is a known cause of fetal death. The immune system and particularly natural killer cells (NK) are known to play a key role in the clearance of several viruses in healthy adults. Whether decidual NK cells (dNK), present in the pregnant uterus, have a role during HCMV infection is not known. We analyze changes in dNK cell function and phenotype in the presence of HCMV-infected targets in an autologous setting. We demonstrate the acquisition of cytotoxic profile which is associated with changes in dNK cell receptor repertoire and cytokine production. Finally, we find that dNK cells are able to sense HCMV infection, migrate and infiltrate infected tissues both in tissular organ culture and in situ in infected placenta. Together our results present the first report demonstrating the involvement of dNK cells in controlling HCMV infection.