BDCA2/FcεRIγ Complex Signals through a Novel BCR-Like Pathway in Human Plasmacytoid Dendritic Cells

Abstract

Dendritic cells are equipped with lectin receptors to sense the extracellular environment and modulate cellular responses. Human plasmacytoid dendritic cells (pDCs) uniquely express blood dendritic cell antigen 2 (BDCA2) protein, a C-type lectin lacking an identifiable signaling motif. We demonstrate here that BDCA2 forms a complex with the transmembrane adapter FcεRIγ. Through pathway analysis, we identified a comprehensive signaling machinery in human pDCs, similar to that which operates downstream of the B cell receptor (BCR), which is distinct from the system involved in T cell receptor (TCR) signaling. BDCA2 crosslinking resulted in the activation of the BCR-like cascade, which potently suppressed the ability of pDCs to produce type I interferon and other cytokines in response to Toll-like receptor ligands. Therefore, by associating with FcεRIγ, BDCA2 activates a novel BCR-like signaling pathway to regulate the immune functions of pDCs. Dendritic cells (DCs) are specialized sentinels in the immune system that detect invading pathogens and, upon activation, initiate immune responses. DCs express C-type lectin receptors on their surface, which facilitate antigen capture. A distinct population of DCs, called plasmacytoid DCs (pDCs), display an extraordinary ability to rapidly make huge amounts of antiviral interferon (IFN) against viral infections. Human pDCs uniquely express a C-type lectin named BDCA2 that potently regulates pDCs function, yet the mechanism of how BDCA2 transduces signals is unknown. We show here that BDCA2 forms a complex with the transmembrane adapter FcεRIγ. Using signaling pathway analysis, we discovered a comprehensive signaling machinery in human pDCs, similar to that which operates downstream of B cell receptors (BCRs), but distinct from the pathway involved in T cell receptor signaling. By associating with FcεRIγ, BDCA2 activates a novel BCR-like signaling pathway to regulate the immune functions of pDCs. Since several pDC receptors use this pathway to modulate IFN and cytokine responses, these findings will guide more studies on how pDCs are regulated. Such mechanisms may lead to potential therapeutic interventions in autoimmune diseases involving hyperactivated pDCs, such as systemic lupus erythematosus and psoriasis.