Activation of human plasmacytoid dendritic cells by TLR9 impairs Fc gammaRII-mediated uptake of immune complexes and presentation by MHC class II.
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.
Benitez-Ribas
Daniel
D
Department of Tumor Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Tacken
Paul
P
Punt
Cornelis J A
CJ
de Vries
I Jolanda M
IJ
Figdor
Carl G
CG
D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology*; D000936:Antigen-Antibody Complex / Q000276:immunology* / Q000378:metabolism; D000941:Antigens / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D011992:Endosomes / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000276:immunology* / Q000378:metabolism
D000936:Antigen-Antibody Complex; D000941:Antigens; C408982:CPG-oligonucleotide; C513200:CpG-A 2336; C080568:Fc gamma receptor IIA; D000949:Histocompatibility Antigens Class II; D007370:Interferon Type I; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D017452:Receptors, IgG; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9