CD303 (BDCA-2) mediated inhibition of interferon type I production in plasmacytoid dendritic cells is linked to SYK, BLNK and PKC delta signaling (89.25)

Abstract

Abstract CD303 is a calcium dependent type II lectin also known as Blood-Dendritic-Cell-Antigen-2 (BDCA-2) specifically expressed by human plasmacytoid dendritic cells (PDC). We have previously shown that monoclonal antibody (mAb) ligation of CD303 induces mAb endocytosis, calcium mobilization, protein tyrosine phosphorylation and inhibition of type I interferon (IFN I) production in stimulated PDC. Here we show that CD303 signaling and internalization in many aspects resembles B cell receptor (BCR) signaling and internalization. Instead of CD79a and CD79b, CD303 appears to use the Fc-receptor-common-gamma-chain as transmembrane adaptor protein. Like BCR signaling, CD303 triggering leads to SYK and BLNK phosphorylation. Signal transduction most likely involves activation of the phospholipase C-gamma 2, the phosphoinositide-3 kinase and the protein kinase C delta. Therefore, inhibition of IFN I production in stimulated PDC can be mimicked by PMA. Western blotting and peptide mass fingerprinting show that tyrosine phosphorylation occurs at cytoskeletal proteins (actin, alpha/beta-tubulin, profilin, alpha-actinin), proteasome activator subunit and the clathrin heavy chain, indicating clathrin-mediated endocytosis and vesicle trafficking. Finally, CD303 triggering inhibits TNF-alpha and CpG ODN-induced NF-kappa B activation in PDC.