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Receptors and Contributes to Acquisition of T Cell Immunity1
* Department of Molecular Microbiology and Immunology and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033; and
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
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 Fc
RIII, and immature dendritic cells (DC) become activated after incubation with HPV VLP; however, it is unclear whether FcR on DC are involved. In mice, FcRII and FcRIII are homologous and bind similar ligands. In this study, we show that binding and uptake of VLP by DC from FcRII, FcRIII, and FcRII/III-deficient mice are reduced by up to 50% compared with wild-type mice. Additionally, maturation of murine DC from FcRII/III-deficient mice by VLP is also reduced, indicating that DC maturation, and thus Ag presentation, is diminished in the absence of expression of FcR. To investigate the in vivo contribution of FcR in the induction of cellular immunity, FcR 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- ELISPOT, and cytotoxicity assays. All readouts indicated that the frequency of E7-specific CD4+ and CD8+ T cells induced in all FcR-deficient mice after immunization with cVLP was significantly diminished. Based on these results, we propose that the low-affinity FcR 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants R01 CA74397 and P01 CA97296, and the V and Whittier Foundations (to W.M.K.). D.M.D.S. was supported by National Institutes of Health Postdoctoral Fellowship T32 CA09659 and the University of Southern California Norris Cancer Center Postdoctoral Scholarship Program. W.M.K. holds the Walter A. Richter Cancer Research Chair.
2 Address correspondence and reprint requests to Dr. W. Martin Kast, Norris Comprehensive Cancer Center, Zilkha Institute Building, Room 245, University of Southern California, 1501 San Pablo Street, MC 2821, Los Angeles, CA 90033. E-mail address: mkast{at}usc.edu
3 Abbreviations used in this paper: HPV, human papillomavirus; BMDC, bone marrow-derived dendritic cell; CMI, cell-mediated immunity; VLP, virus-like particle; cVLP, chimeric VLP; DC, dendritic cell; IC, immune complex; MFI, mean fluorescence intensity; SEB, Staphylococcus enterotoxin B; wt, wild type.
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