Uptake of human papillomavirus virus-like particles by dendritic cells is mediated by Fcγ receptors and contributes to acquisition of T cell immunity

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 FcyRIII, and immature dendritic cells (DC) become activated after incubation with HPV VLP; however, it is unclear whether Fc gamma R on DC are involved. In mice, Fc gamma RII and FcyRIII are homologous and bind similar ligands. In this study, we show that binding and uptake of VLP by DC from Fc gamma RII, Fc gamma RIII, and Fc gamma RII-deficient mice are reduced by up to 50% compared with wild-type mice. Additionally, maturation of murine DC from Fc gamma RII/III-deficient mice by VLP is also reduced, indicating that DC maturation, and thus Ag presentation, is diminished in the absence of expression of Fc gamma R. To investigate the in vivo contribution of Fc gamma R in the induction of cellular immunity, Fc gamma R 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 Fc gamma R-deficient mice after immunization with cVLP was significantly diminished. Based on these results, we propose that the low-affinity Fc gamma R 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.