title: Uptake of human papillomavirus virus-like particles by dendritic cells is mediated by Fcgamma receptors and contributes to acquisition of T cell immunity.
abstract: Chimeric human papillomavirus virus-like particles (HPV cVLP) are immunogens able to elicit potent CTL responses in mice against HPV16-transformed tumors; however, the mechanism of T cell priming has remained elusive. HPV VLP bind to human MHC class II-positive APCs through interaction with FcgammaRIII, and immature dendritic cells (DC) become activated after incubation with HPV VLP; however, it is unclear whether FcgammaR on DC are involved. In mice, FcgammaRII and FcgammaRIII are homologous and bind similar ligands. In this study, we show that binding and uptake of VLP by DC from FcgammaRII, FcgammaRIII, and FcgammaRII/III-deficient mice are reduced by up to 50% compared with wild-type mice. Additionally, maturation of murine DC from FcgammaRII/III-deficient mice by VLP is also reduced, indicating that DC maturation, and thus Ag presentation, is diminished in the absence of expression of FcgammaR. To investigate the in vivo contribution of FcgammaR in the induction of cellular immunity, FcgammaR single- and double-knockout mice were immunized with HPV16 L1/L2-E7 cVLP, and the frequency of E7-specific T cells was analyzed by tetramer binding, IFN-gamma ELISPOT, and cytotoxicity assays. All readouts indicated that the frequency of E7-specific CD4(+) and CD8(+) T cells induced in all FcgammaR-deficient mice after immunization with cVLP was significantly diminished. Based on these results, we propose that the low-affinity FcgammaR contribute to the high immunogenicity of HPV VLP during T cell priming by targeting VLP to DC and inducing a maturation state of the DC that facilitates Ag presentation to and activation of naive T cells.
authors.affiliation: Department of Molecular Microbiology and Immunology and Norris Comprehensive Cancer Center, University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90033, USA.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Da Silva
authors.forename: Steven C
authors.initials: SC
authors.lastname: Fausch
authors.forename: J Sjef
authors.initials: JS
authors.lastname: Verbeek
authors.forename: W Martin
authors.initials: WM
authors.lastname: Kast
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D003713:Dendritic Cells / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D052162:Human papillomavirus 16 / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014771:Virion / Q000276:immunology*
chemical_list: D000949:Histocompatibility Antigens Class II; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D017452:Receptors, IgG; C059731:oncogene protein E7, Human papillomavirus type 16