BDCA-2 signaling inhibits TLR-9-agonist-induced plasmacytoid dendritic cell activation and antigen presentation.
Plasmacytoid dendritic cells (PDCs) express Toll-like receptor (TLR) 9, which mediates recognition of microbial DNA during infection or self-DNA in autoimmune diseases. Triggering TLR-9 in PDC induces either maturation (lysosomal TLR-9 triggering) or type I interferon (IFN-I) production (endosomal TLR-9 triggering). PDCs also express BDCA-2 (CD303), a C-type lectin receptor (CLR) unique to these cells. CLRs appear to function in innate immunity and microbial recognition, and may cooperate with TLRs to fine-tune inflammatory responses. It has been shown that anti-BDCA-2 monoclonal antibody is internalized by PDC for antigen presentation and inhibits TLR-9 induced IFN-I expression. Here we investigated the cross-talk between BDCA-2 and TLR-9-signaling during PDC maturation and antigen presentation. We found that BDCA-2-induced signaling in PDCs inhibits up-regulation of CD86 and CD40 molecules in CpG-activated PDCs, but not in CD40L-activated PDCs. Furthermore, triggering of BDCA-2 diminished the ability of CpG- and CD40L-stimulated PDCs to process and present antigen to antigen-specific autologous memory T cells. This study demonstrates that BDCA-2 represents an attractive target for clinical immunotherapy of IFN-I dependent autoimmune diseases influencing both, IFN-I production and antigen-specific T-cell stimulation by PDC.
Jähn
Peter S
PS
Department of Research and Development, Miltenyi Biotec GmbH, Friedrich-Ebert-Strasse 68, D-51429 Bergisch Gladbach, Germany. peterj@miltenyibiotec.de
Zänker
Kurt S
KS
Schmitz
Jürgen
J
Dzionek
Andrzej
A
D017951:Antigen Presentation / Q000276:immunology; D015153:Blotting, Western; D023201:CD40 Ligand / Q000276:immunology; D018899:CpG Islands / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007111:Immunity, Cellular; D037181:Lectins, C-Type / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D018613:Microscopy, Confocal; D011971:Receptors, Immunologic / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology*
C443299:CLEC4C protein, human; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D023201:CD40 Ligand