Plasmacytoid DCs (pDCs) are a distinct population of DCs in the peripheral blood and secondary lymphoid organs and are characterized by their plasma cell–like morphology and unique surface receptor phenotype (1
). These cells play an important role in innate antiviral immunity by rapidly secreting abundant type I IFNs (IFNα, β, ω, λ) after exposure to various DNA and RNA viruses (1
). Type I IFNs produced by pDCs promote the function of NK cells, B cells, T cells, and myeloid DCs (mDCs) during the initial immune response (3
). After activation, pDCs differentiate into a unique type of mature DCs, capable of directing T cell responses with considerable flexibility (3
). Thus, pDCs represent a critical link between innate and adaptive immune responses.
The unique ability of pDCs to sense and respond rigorously to microbes by rapidly producing large amounts of type I IFN is underlined by their expression, in contrast with mDCs and other immune cells, of a selective set of toll-like receptors (TLRs), in particular TLR7 and TLR9 (6
). Recent studies have revealed an intracellular multiprotein complex that likely includes TLR9/7–MyD88–IRAK1/4–TRAF6–IRF7 and a complicated spatiotemporal signaling scheme in pDCs (7
). Because both TLR7 and TLR9 are located in the endosomal compartment of pDCs, how these cells sense the external microenvironment by surface receptors has remained elusive. We, therefore, performed a global gene expression analysis of human pDCs, in comparison with the other major human immune cell types. Human pDCs selectively express ILT7 (also named CD85g and LILRA4) transcripts as well as IL-3R (CD123) and BDCA-2, as previously reported (9
ILT7 is a member of the immunoglobulin-like transcripts (ILTs), or leukocyte immunoglobulin-like receptor (LIR) gene family (12
), which comprises at least 13 loci. ILTs are predominantly expressed on the surface of myelomonocytic cells, including macrophages and DCs. Although the extracellular Ig domains are responsible for ligand binding, the residues within the transmembrane and cytoplasmic domains define two functional classes of ILTs: the inhibitory ILTs contain the immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic domain, whereas the activating ILTs lack any intrinsic signaling motifs and rely on association with transmembrane adapter proteins bearing immunoreceptor-based tyrosine activation motif (ITAM). Certain ILTs, such as ILT2 and ILT4, bind to classical and nonclassical MHC class I proteins (13
). The ITIM-containing ILT2 inhibits signaling through the TCR in T cells (14
) and enhances the inhibitory effects of killer cell Ig–like receptors (KIRs) in NK cells (13
). In contrast, ILT1 associates with Fc
RIγ and activates eosinophils to release cytotoxic granule proteins, cytokines, and lipid mediators (15
ILT7 encodes a surface receptor that is preferentially transcribed by human pDCs. This molecule contains four extracellular Ig domains and has a positively charged residue within the transmembrane region, which potentially allows it to associate with membrane-anchored adapter proteins. In this study, we report that ILT7 and Fc
RIγ form a receptor complex that is specific for human pDCs and transduces ITAM-mediated signals that negatively modulate TLR-induced type I IFN production by human pDCs.