Plasmacytoid Dendritic Cell Receptor BDCA2/FcεRγ Complex Uses BCR-like Signaling Cascade to Modulate Toll-Like Receptor Responses (89.20)

Abstract BDCA2 is a C-type lectin uniquely expressed by human plasmacytoid dendritic cells (pDCs). Ligation of this receptor by mAb inhibits Toll-like receptor (TLR)-mediated type I IFN responses by pDCs. However, it remains unclear how BDCA2 signals. We demonstrate here that BDCA2 forms a receptor complex with the transmembrane adapter FcεRIγ. Furthermore, pDCs express a comprehensive signaling machinery similar to that of the B cell receptor (BCR), which is distinct from that involved in T cell receptor (TCR) signaling. BDCA2 crosslinking resulted in the activation of BCR-like signal cascade in pDCs including phosphorylation of Syk and Src family kinases, as well as adapter molecule BLNK, leading to NFAT activation and calcium flux. This potently suppressed the ability of pDCs to produce IFN and other cytokines in response to both TLR7 and TLR9 ligands. Therefore, BDCA2 negatively regulates pDCs’ innate immune functions by associating with FcεRIγ and activating a BCR-like signaling pathway.