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Activation of Human Plasmacytoid Dendritic Cells by TLR9 Impairs FcRII-Mediated Uptake of Immune Complexes and Presentation by MHC Class II

Daniel Benitez-Ribas^*, Paul Tacken^*, Cornelis J. A. Punt, I. Jolanda M. de Vries^1,*, and Carl G. Figdor^*

^* Department of Tumor Immunology, Department of Medical Oncology, and Department of Pediatric Oncology, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands

Human plasmacytoid dendritic cells (pDCs)² exploit Ag uptake receptors like CD32a for internalization of exogenous Ags. Activation of pDC by TLR9 ligand CpG-C induces strong maturation. Surprisingly, we observed that CpG-C-stimulated pDCs showed impaired Ag-specific T cell proliferation whereas the induction of allogeneic T cell proliferation was not affected. We demonstrated that signals from TLR9 caused a rapid down-regulation of the capacity of pDC to take-up Ab-Ag complexes without altering their CD32a expression, thus explaining the reduced Ag presentation. The recent contrasting biological responses that were observed upon TLR9 ligation in pDCs prompted us to study the effect of several TLR9 ligands. We observed that type I IFN-inducer CpG-A, localizing in the early endosomal compartment, did not affect CD32a function, whereas CpGs localizing in the late endosomes and inducing pDC maturation clearly inhibited CD32a-mediated Ag uptake and presentation. We conclude that TLR9 ligands not only determine the type of response, i.e., type I IFN production (innate immunity) or maturation (adaptive immunity), but also directly affect Ag presentation capacity of pDCs. We hypothesize that pDC, once activated via TLR9-ligands reaching the late endosomes, can only present initially sampled Ags and thus are protected from uptake and processing of additional potential self-Ags.

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 Address correspondence and reprint requests to Dr. Jolanda De Vries, Radboud University, Nijmegen, PO Box 9101, The Netherlands. E-mail address: j.devries{at}ncmls.ru.nl

² Abbreviations used in this paper: pDC, plasmacytoid dendritic cell; KLH, keyhole limpet hemocyanin; ODN, oligodeoxynucleotide; moDC, monocyte-derived DC.

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The JI 2008 181: 5179-5180. [Full Text]