title: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, UMR 1043, Toulouse, France.
authors.forename: Johan
authors.initials: J
authors.lastname: Siewiera
authors.forename: Hicham
authors.initials: H
authors.lastname: El Costa
authors.forename: Julie
authors.initials: J
authors.lastname: Tabiasco
authors.forename: Alain
authors.initials: A
authors.lastname: Berrebi
authors.forename: Géraldine
authors.initials: G
authors.lastname: Cartron
authors.forename: Philippe
authors.initials: P
authors.lastname: Le Bouteiller
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouteiller
authors.forename: Nabila
authors.initials: N
authors.lastname: Jabrane-Ferrat
mesh_terms: D019002:CD56 Antigen / Q000378:metabolism; D002460:Cell Line; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000151:congenital / Q000276:immunology* / Q000378:metabolism; D003656:Decidua / Q000166:cytology / Q000276:immunology* / Q000821:virology; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000276:immunology / Q000378:metabolism; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000276:immunology / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism; D010929:Placentation; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014599:Uterus
chemical_list: D019002:CD56 Antigen; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C527059:KLRC2 protein, human; C527085:KLRK1 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D055655:NK Cell Lectin-Like Receptor Subfamily K; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human