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

Wei Cao,Gokuran Watanabe,Lewis L Lanier,Yong-Jun Liu,Laura Bover,Musheng Bao,David B Rosen,Li Zhang,Shizuo Akira

doi:10.1371/journal.pbio.0050248

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 FcɛRIγ. 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 FcɛRIγ, BDCA2 activates a novel BCR-like signaling pathway to regulate the immune functions of pDCs.

Highlights

Dendritic cells (DCs) are specialized sentinels in the immune system that detect invading pathogens and pathological damages of the host
We show here that blood dendritic cell antigen 2 (BDCA2) forms a complex with the transmembrane adapter FceRIc
We discovered a comprehensive signaling machinery in human plasmacytoid DC (pDC), similar to that which operates downstream of B cell receptors (BCRs), but distinct from the pathway involved in T cell receptor signaling

Summary

Introduction

Dendritic cells (DCs) are specialized sentinels in the immune system that detect invading pathogens and pathological damages of the host. DCs instruct appropriate and effective immune responses [1,2,3] Their extraordinary ability to capture antigens (self or foreign) is largely mediated by the collective expression of C-type lectin receptors (CLRs) on the cell surface [4,5]. DC subsets display a discrete expression profile of C-type lectins—CD8þ DCs express DEC-205 (CD205), whereas CD8À DCs express dendritic cell immunoreceptor 2 (DCIR2), dendritic cell immunoactivating receptor (DCAR), Dectin-1, Dectin-2, DCIR3, and DC-SIGN [6] This expression profile, in conjunction with the polarized expression of antigen processing and presentation machinery, contributes to the intrinsic functional difference between the DC subsets in regulating immunity [6]. Besides tissue DCs, macrophage, myeloid DCs (mDCs) and monocytes express a number of CLRs, such as Dectin-1, macrophage mannose receptor (MMR), and DCIR [3,4]

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