CD303 (BDCA‐2) signals in plasmacytoid dendritic cells via a BCR‐like signalosome involving Syk, Slp65 and PLCγ2

Abstract Plasmacytoid dendritic cells (PDC) are the main type I interferon (IFN‐I) producers and play a central role in innate and adaptive immunity. CD303 (BDCA‐2) is a type II c‐type lectin specifically expressed by human PDC. CD303 signaling induces tyrosine phosphorylation and Src kinase dependent calcium influx. Cross‐linking CD303 results in the inhibition of IFN‐I production in stimulated PDC. Here, we demonstrate that PDC express a signalosome similar to the BCR signalosome, consisting of Lyn, Syk, Btk, Slp65 (Blnk) and PLCγ2. CD303 associates with the signaling adapter FcR γ‐chain. Triggering CD303 leads to tyrosine phosphorylation of Syk, Slp65, PLCγ2 and cytoskeletal proteins. Analogous to BCR signaling, CD303 signaling is likely linked with its internalization by clathrin‐mediated endocytosis. Furthermore, CD303 signaling leads to reduced levels of transcripts for IFN‐I genes and IFN‐I‐responsive genes, indicating that the inhibition of IFN‐I production by stimulated PDC is at least partially regulated at the transcriptional level. These results support a possible therapeutic value of an anti‐CD303 mAb strategy, since the production of IFN‐I by PDC is considered to be a major pathophysiological factor in systemic lupus erythematosus patients. See accompanying commentary at http://dx.doi.org/10.1002/eji200737944