The Vesicular Traffic System in Plasmacytoid Dendritic Cells as a Target for Immune Regulation

Abstract

Plasmacytoid dendritic cells (pDCs) are a unique immune cell type that produces a vast amount of interferon (IFN)-α in response to virus-derived DNA and RNA through Toll-like receptor (TLR) 9 and TLR7, respectively. Nucleic acids derived from self-cells also stimulate pDCs to produce IFN-α in certain conditions, and is implicated in the pathogenesis of inflammatory disorders such as lupus and psoriasis. Recent studies have revealed that elaborate vesicular trafficking machinery in pDCs is the key to the prodigious IFN-α production. Upon stimulation, the nucleic acid-sensing TLRs traffic from the endoplasmic reticulum to the endolysosomal compartments together with a multiple membrane-spanning protein UNC93B1 (Unc-93 homolog B1). Aggregated DNA endocytosed by pDCs is retained in early endosomes for an extended period of time or moves to lysosome-related organelles well-equipped with the machinery for IFN-α production. The nucleic acid then meets the TLR in endolysosomes in a way that produces a large amount of IFN-α. Such exquisite ‘receptor transport’ and ‘ligand transport’ systems are vulnerable to pharmacological interventions, the proteasome inhibitor bortezomib, and the tyrosine kinase inhibitor dasatinib, respectively. Elucidating precise molecular mechanisms by which to control vesicular trafficking of TLRs and their ligands in pDCs will reveal new aspects of physiology of vesicular traffic and novel targets to treat pDC-mediated inflammatory disorders.