title: Human papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion.
abstract: Human papillomavirus (HPV) infections account for more than 50% of infection-linked cancers in women worldwide. The immune system controls, at least partially, viral infection and around 90% of HPV-infected women clear the virus within two years. However, it remains unclear which immune cells are implicated in this process and no study has evaluated the direct interaction between HPVs and NK cells, a key player in host resistance to viruses and tumors. We demonstrated an NK-cell infiltration in HPV-associated preneoplastic cervical lesions. Since HPVs cannot grow in vitro, virus-like particles (VLPs) were used as a model for studying the NK-cell response against the virus. Interestingly, NK cells displayed higher cytotoxic activity and cytokine production (TNF-α and IFN-γ) in the presence of HPV-VLPs. Using flow cytometry and microscopy, we observed that NK-cell stimulation was linked to rapid VLP entry into these cells by macropinocytosis. Using CD16(+)  and CD16(-)  NK-cell lines and a CD16-blocking antibody, we demonstrated that CD16 is necessary for HPV-VLP internalization, as well as for degranulation and cytokine production. Thus, we show for the first time that NK cells interact with HPVs and can participate in the immune response against HPV-induced lesions.
authors.affiliation: Laboratory of Experimental Pathology, University of Liège, Liège, Belgium.
authors.forename: Virginie M
authors.initials: VM
authors.lastname: Renoux
authors.forename: Bettina
authors.initials: B
authors.lastname: Bisig
authors.forename: Inge
authors.initials: I
authors.lastname: Langers
authors.forename: Estelle
authors.initials: E
authors.lastname: Dortu
authors.forename: Béatrice
authors.initials: B
authors.lastname: Clémenceau
authors.forename: Marc
authors.initials: M
authors.lastname: Thiry
authors.forename: Christophe
authors.initials: C
authors.lastname: Deroanne
authors.forename: Alain
authors.initials: A
authors.lastname: Colige
authors.forename: Jacques
authors.initials: J
authors.lastname: Boniver
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jacobs
mesh_terms: D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D018613:Microscopy, Confocal; D027383:Papillomaviridae / Q000276:immunology*; D030361:Papillomavirus Infections / Q000276:immunology; D011230:Precancerous Conditions / Q000276:immunology / Q000378:metabolism / Q000821:virology; D017452:Receptors, IgG / Q000096:biosynthesis / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D053586:Virus Internalization; D002578:Uterine Cervical Dysplasia / Q000276:immunology / Q000378:metabolism / Q000821:virology
chemical_list: D016207:Cytokines; D017452:Receptors, IgG