Dendritic Cell Immunoactivating Receptor, a Novel C-type Lectin Immunoreceptor, Acts as an Activating Receptor through Association with Fc Receptor γ Chain

Abstract

An increasing number of C-type lectin receptors are being discovered on dendritic cells, but their signaling abilities and underlying mechanisms require further definition. Among these, dendritic cell immunoreceptor (DCIR) induces negative signals through an inhibitory immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic tail. Here we identify a novel C-type lectin receptor, dendritic cell immunoactivating receptor (DCAR), whose extracellular lectin domain is highly homologous to that of DCIR. DCAR is expressed similarly in tissues to DCIR, but its short cytoplasmic portion lacks signaling motifs like ITIM. However, a positively charged arginine residue is present in the transmembrane region of the DCAR, which may explain its association with Fc receptor ␥ chain and its stable expression on the cell surface. Furthermore, cross-linking of DCAR in the presence of ␥ chain activates calcium mobilization and tyrosine phosphorylation of cellular proteins. These signals are mediated by the immunoreceptor tyrosine-based activating motif (ITAM) of the ␥ chain. Thus, DCAR is closely related to DCIR, but it introduces activating signals into antigen-presenting cells through its physical and functional association with ITAM-bearing ␥ chain. The identification of this activating immunoreceptor provides an example of signaling via a dendritic cell-expressed C-type lectin receptor.Paired immunoreceptors (1-4) are composed of an immunoreceptor tyrosine-based inhibitory motif (ITIM) 1 -bearing inhibitory receptor and an immunoreceptor tyrosine-based activating motif (ITAM)-bearing activating receptor. Such pairs of receptors, when expressed on the same cell, allow for a balance between positive and negative cell signaling. In most cases, activating receptors are formed as complexes of a ligand-binding subunit with a short cytoplasmic tail and an ITAM-bearing signal-transducing subunit. This signal-transducing subunit can be shared by several receptors. These activating receptors were first identified on effector cells such as natural killer (NK), T, B, and mast cells and subsequently detected on myeloid cells including granulocytes, macrophages, and dendritic cells (DC). Now it is evident that such receptors are used rather ubiquitously, including in platelets (5) and even nonhematopoietic cells (6). Based on their domain structures, these receptors are divided into two subgroups, Ig superfamily and Ca 2ϩ -dependent (C-type) lectin family. Besides their structural similarity, the genes for these families are clustered (e.g. the Ig superfamily in the leukocyte receptor complex on human chromosome 19 or syntenic mouse chromosome 7, and the C-type lectin family in the NK gene complex (NKC) on human chromosome 12 or syntenic mouse chromosome 6, respectively) (7).On the other hand, there have been many C-type lectin receptors detected on DC. Based on their molecular structures, they include two types of receptors: type I C-type lectin as a type I transmembrane protein with several carbohydrate recognition domains ...

Enhanced Dendritic Cell-Induced Immune Responses Mediated by the Novel C-Type Lectin Receptor mDCAR1

“…The expression of mDCIR, mDCIR2, mDCIR3, mDCIR4, mDCAR, and mDCAR1 has thus far been demonstrated only at the mRNA level (6,20,21). The mRNA expression of mDCIR2 and mDCAR1 on NK cells, based on analysis of cells derived from spleen (6), contradicts both the protein expression pattern demonstrated here for mDCAR1 using specific mAb and that described for mDCIR2 (22).…”

“…As revealed by in silico protein analysis, mDCAR1 was found to lack such signal transduction motifs. Closely related CLRS, such as CD303, mDCAR, and further Dectin-2 and Mincle, have been reported to signal via an associated ITAM-bearing FcR ␥-chain (21,(45)(46)(47). Therefore, interaction of mDCAR1 with FcR ␥-chain is highly expected but needs further verification.…”

The rat antigen-presenting lectin-like receptor complex influences innate immunity and development of infectious diseases

“…[5][6][7] The ligands and functions of the receptors remain unknown, but the receptor type has been implicated in diverse functions, such as microbial pattern recognition, cellular adhesion and migration, antigen uptake and presentation, T cell co-stimulation, and signal transduction through immunoreceptor tyrosine-based inhibitory or activating motifs (ITIMs and ITAMs, respectively). [8][9][10][11] Interestingly, we observed earlier that APLEC regulates clinical phenotypes in RA models induced by nonimmunogenic structures that activate the innate immune system, for example, incomplete Freund's adjuvant oil and yeast b-glucan. 5 Herein, we tested the hypothesis that APLEC might also regulate infectious diseases and innate macrophage reactivity.…”

CD85j (Leukocyte Ig-Like Receptor-1/Ig-Like Transcript 2) Inhibits Human Osteoclast-Associated Receptor-Mediated Activation of Human Dendritic Cells

“…This growing family of receptors was described first in lymphocytes (14 -16). However, in recent years, an increasing number of receptors that are members of the lectin family and of the Ig superfamily and are linked to ITAM/ITIM signaling have been described on myeloid cells and DCs, such as Fc␥R, C-type lectin receptors (DC immunoactivating receptor), Ig-like transcript (ILT)3, ILT4, and FDF03 (17)(18)(19)(20)(21)(22).…”