Dendritic Cell Immunoreceptor Research Articles

Therapeutic targets for rheumatoid arthritis: lessons from animal models

We have generated two RA models, human T-cell leukemia virus type I (HTLV-I) transgenic mice and IL-1 receptor antagonist (Ra)-deficient (KO) mice, to elucidate the pathogenic mechanisms of the disease. Both models spontaneously developed arthritis closely resembling that of RA in humans. We found that TNF-, but not IL-6-, deficiency suppressed development of arthritis in IL-1Ra KO mice, while IL-6 but not TNF was involved in the HTLV-I transgenic mouse model [1]. IL-17 was important in both models. These observations suggest that pathogenic roles of IL-6 and TNF are different and both TNF, IL-6, and IL-17 are good targets for therapeutics. We found that the expression of C-type lectin receptor (CLR) genes was augmented in the affected joints of these models using DNA microarrays. Dendritic cell immunoreceptor (DCIR) is one of such CLRs with a carbohydrate recognition domain in their extracellular carboxy terminus and an ITIM in its intracellular amino terminus. Because human shared syntenic locus containing the Dcir gene is linked to several autoimmune diseases including RA and SLE, we have generated Dcir KO mice to examine the roles of this gene in the immune system. We found that aged Dcir KO mice spontaneously developed sialadenitis and enthesitis associated with elevated serum autoantibodies [2]. DCs were excessively expanded in Dcir KO mice after aging. Dcir KO mouse-derived bone marrow cells (BMCs) differentiated into DCs more efficiently than did wild-type BMCs upon treatment with GM-CSF, owing to enhanced STAT-5 phosphorylation. These findings indicate that DCIR is crucial for maintaining the homeostasis of the immune system, suggesting that Dcir is one of novel targets for the treatment of RA. We have also found that the expression of Muratin1, which encodes uncharacterized and secreted protein, is specifically up-regulated in affected joins of both models. Interestingly, the development of collagen-induced arthritis was markedly exacerbated in Muratin1 KO mice. I would like to discuss the roles of Muratin-1 in the development of arthritis.

Dendritic cell immunoreceptor (DCIR) is associated with anti-cyclic citrullinated peptides (anti-CCP) antibody - negative rheumatoid arthritis in Chinese Han population

Dendritic cell immunoreceptor (DCIR) is associated with anti-cyclic citrullinated peptides (anti-CCP) antibody - negative rheumatoid arthritis in Chinese Han population

Innate signaling in HIV-1 infection of dendritic cells

This review summarizes the current knowledge of innate signaling events that are involved in HIV-1 infection. We here focus on dendritic cells, which are among the first cells that encounter HIV-1 after exposure. HIV-1 triggers multiple pattern recognition receptors on dendritic cells that facilitate infection and transmission to T cells. Triggering of the C-type lectin DC-SIGN induces signals that promote HIV-1 replication in dendritic cells and transmission to T cells. Similarly, dendritic cell immunoreceptor has been shown to bind HIV-1 and facilitate transmission to T cells. The cytosolic sensors TRIM5 and cyclophilin A recognize capsid proteins and activate antiviral responses to prevent HIV-1 infection. Moreover, activation of mammalian target of rapamycin (mTOR) by HIV downregulates autophagy preventing adaptive immune responses. Dendritic cells express an array of pattern recognition receptors that are involved in HIV-1 infection. However, HIV-1 dampens signaling by these receptors leading to suppressed responses or takes advantage of their signaling for its own benefit.

ITAM signaling in dendritic cells controls T helper cell priming by regulating MHC class II recycling

AbstractImmature dendritic cells (DCs) specialize in antigen capture and maintain a highly dynamic pool of intracellular major histocompatibility complex class II (MHCII) that continuously recycles from peptide loading compartments to the plasma membrane and back again. This process facilitates sampling of environmental antigens for presentation to T helper cells. Here, we show that a signaling pathway mediated by the DC immunoreceptor tyrosine-based activation motif (ITAM)–containing adaptors (DAP12 and FcRγ) and Vav family guanine nucleotide exchange factors controls the half-life of surface peptide-MHCII (pMHCII) complexes and is critical for CD4 T-cell triggering in vitro. Strikingly, mice with disrupted DC ITAMs show defective T helper cell priming in vivo and are protected from experimental autoimmune encephalitis. Mechanistically, we show that deficiency in ITAM signaling results in increased pMHCII internalization, impaired recycling, and an accumulation of ubiquitinated MHCII species that are prematurely degraded in lysosomes. We propose a novel mechanism for control of T helper cell priming.

Cross-priming CD8+ T cells by targeting antigens to human dendritic cells through DCIR

AbstractWe evaluated human CD8+ T-cell responses generated by targeting antigens to dendritic cells (DCs) through various lectin receptors. We found the immunoreceptor tyrosine-based inhibitory motif-containing DC immunoreceptor (DCIR) to mediate potent cross-presentation. A single exposure to a low dose of anti-DCIR–antigen conjugate initiated antigen-specific CD8+ T-cell immunity by all human DC subsets including ex vivo–generated DCs, skin-isolated Langerhans cells, and blood myeloid DCs and plasmacytoid DCs. The delivery of influenza matrix protein (FluMP) through DCIR resulted in expansion of FluMP-specific memory CD8+ T cells. Enhanced specific CD8+ T-cell responses were observed when an antigen was delivered to the DCs via DCIR, compared with those induced by a free antigen, or antigen conjugated to a control monoclonal antibody or delivered via DC-SIGN, another lectin receptor. DCIR targeting also induced primary CD8+ T-cell responses against self (MART-1) and viral (HIV gag) antigens. Addition of Toll-like receptor (TLR) 7/8 agonist enhanced DCIR-mediated cross-presentation as well as cross-priming, particularly when combined with a CD40 signal. TLR7/8 activation was associated with increased expansion of the primed CD8+ T cells, high production of interferon-γ and tumor necrosis factor-α, and reduced levels of type 2–associated cytokines. Thus, antigen targeting via the human DCIR receptor allows activation of specific CD8+ T-cell immunity.

Immunomodulation by duck defensin, Apl_AvBD2: In vitro dendritic cell immunoreceptor (DCIR) mRNA suppression, and B- and T-lymphocyte chemotaxis

The present study analyzed the immunomodulatory potential of a newly identified duck β-defensin, Apl_AvBD2. Recombinant Apl_AvBD2 expressed in HEK293T cells induced a concentration dependent in vitro migration of duck splenocytes, and spleen B- and T-lymphocytes, which was specifically inhibited by anti-Apl_AvBD2 polyclonal antibodies. Among the transcripts of 13 immunologically important genes analyzed in cultured splenocytes for the early immunomodulatory effect of Apl_AvBD2, dendritic cell immunoreceptor (DCIR) mRNA was found to be significantly down-regulated. However, there were no major changes in the expression levels of transcripts for cell surface proteins (MHC I, MHC II 2 β-chain, TCR-β, TLR-7, DCAR, CD44, and CD58) and cytokines (IL-2, IFN-γ, RANTES, MIP-1β-like and MCP-1 like chemokines). Our results reveal chemotactic and immunomodulatory properties of Apl_AvBD2, two important functions that would help in employing this protein as a molecular adjuvant with avian vaccines.

DCIR is endocytosed into human dendritic cells and inhibits TLR8-mediated cytokine production

C-type lectin receptors (CLRs) expressed on APCs play a pivotal role in the immune system as pattern-recognition and antigen-uptake receptors. In addition, they may signal directly, leading to cytokine production and immune modulation. To this end, some CLRs, like dectin-1 and dendritic cell immunoreceptor (DCIR), contain intracellular ITIMs or ITAMs. In this study, we explored expression and function of the ITIM-containing CLR DCIR on professional APCs. DCIR is expressed on immature and mature monocyte-derived DCs (moDC) but also on monocytes, macrophages, B cells, and freshly isolated myeloid and plasmacytoid DCs. We show that endogenous DCIR is internalized efficiently into human moDC after triggering with DCIR-specific mAb. DCIR internalization is clathrin-dependent and leads to its localization in the endo-/lysosomal compartment, including lysosome-associated membrane protein-1+ lysosomes. DCIR triggering affected neither TLR4- nor TLR8-mediated CD80 and CD86 up-regulation. Interestingly, it did inhibit TLR8-mediated IL-12 and TNF-alpha production significantly, and TLR2-, TLR3-, or TLR4-induced cytokine production was not affected. Collectively, the data presented characterize DCIR as an APC receptor that is endocytosed efficiently in a clathrin-dependent manner and negatively affects TLR8-mediated cytokine production. These data provide further support to the concept of CLR/TLR cross-talk in modulating immune responses.

Differential expression of transcripts for the autoimmunity-related human dendritic cell immunoreceptor

Dendritic cell immunoreceptor (DCIR) deficiency is related to development of autoimmune disorders and DCIR gene polymorphisms are associated with rheumatoid arthritis (RA). We analyzed the mRNA expression from the four known transcripts of DCIR in IFN-gamma-treated human leukocytes together with fine mapping across the locus. RA patients and healthy controls were genotyped for several single nucleotide polymorphisms (SNPs) in DCIR and flanking regions. mRNA expression in peripheral blood mononuclear cells (PBMCs), stimulated with gamma-interferon (IFN-gamma) in vitro, was determined by transcript-specific PCR. Our data reveal that IFN-gamma significantly downregulates the average expression of transcripts DCIR_v1, DCIR_v2, DCIR_v3 and DCIR_v4 (P<0.0001 for v1, P<0.02 for v2, P<0.0001 for v3, P<0.001 for _v4, patients and controls, Wilcoxon signed-rank). The expression of DCIR showed significant association with variations in the gene. Cells with the RA-associated allele rs2024301 exhibit a significant increase in the expression of DCIR_v4. We also present a new fifth isoform lacking exons 2, 3 and 4. This data illustrate that common genetic variations may influence DCIR mRNA expression. We also show that the expression is regulated by the inflammatory mediator IFN-gamma, affecting all four transcripts and that this was independent of genotype.

Targeting DCIR on human plasmacytoid dendritic cells results in antigen presentation and inhibits IFN-α production

AbstractC-type lectin receptors (CLRs) fulfill multiple functions within the immune system by recognition of carbohydrate moieties on foreign or (altered) self-structures. CLRs on myeloid dendritic cells (DCs) have been well characterized as pattern-recognition receptors (PRRs) combining ligand internalization with complex signaling events. Much less is known about CLR expression and function in human plasmacytoid DCs (pDCs), the major type I interferon (IFN) producers. In this study, we demonstrate that, next to the CLR BDCA-2, human pDCs express DC immunoreceptor (DCIR), a CLR with putative immune-inhibitory function, but not dectin-1, mannose receptor, or DC-specific ICAM-3–grabbing nonintegrin. DCIR surface levels are reduced on pDC maturation after TLR9 triggering. Interestingly, DCIR triggering inhibits TLR9-induced IFN-α production while leaving up-regulation of costimulatory molecule expression unaffected. Furthermore, DCIR is readily internalized into pDCs after receptor triggering. We show that DCIR internalization is clathrin-dependent because it can be inhibited by hypertonic shock and dominant-negative dynamin. Importantly, antigens targeted to pDCs via DCIR are presented to T cells. These findings indicate that targeting DCIR on pDCs not only results in efficient antigen presentation but also affects TLR9-induced IFN-α production. Collectively, the data show that targeting of DCIR can modulate human pDC function and may be applied in disease preven-tion and treatment.

Dendritic Cell immuno‐activating receptor 1 – Characterization of a novel member of the C‐type Lectin family

C‐type lectins (CLEC) comprise a superfamily of cell surface proteins, whose multifunctional capacity has been shown to address both, innate and adaptive immune response. Here, we describe mDCAR1 a novel CLEC belonging to the recently defined murine dendritic cell (DC) immuno‐receptor (mDCIR)/DC immuno‐activating receptor (mDCAR) family.mDCAR1 expression was found to be restricted to mononuclear phagocytes in bone marrow. Extensive phenotypical characterization defined them as CCR2−CD62L−CX3CR1+Ly6C− cells, thereby belonging to the recently described ‘resident’ monocytes, which correspond to CD14+ CD16+ human monocytes. In contrast, the CCR2+CD62L+CX3CR1lowLy6C+ ‘inflammatory’ monocytes were mDCAR1−. Noteworthy, in thymus, mDCAR1 expression was found on CD11chighCD8alpha+CD205+CD11b−B220−BP‐1+ lymphoid‐related DC, which play an important role in central tolerance induction.With respect to the classical function of CLEC as antigen uptake receptors for pathogens and self‐proteins, mimicking the ligation of mDCAR1 by labeling with specific mAb shows the internalization of the mDCAR1/ligand complex. Crosslinking of mDCAR1 further initiates signal transduction resulting in tyrosine‐phosphorylation of proteins.The expression pattern of mDCAR1 and the evidence of a classical antigen‐uptake mechanism are first steps to uncover the role of this representative of the CLEC receptor family.

Cellular distribution of the C-type II lectin dendritic cell immunoreceptor (DCIR) and its expression in the rheumatic joint: identification of a subpopulation of DCIR+ T cells

Objective:An association to variations in the dendritic cell immunoreceptor (DCIR) gene with rheumatoid arthritis (RA) was recently shown. However, protein expression of DCIR has so far not been assessed in...

Dcir deficiency causes development of autoimmune diseases in mice due to excess expansion of dendritic cells

The dendritic cell immunoreceptor (official gene symbol Clec4a2, called Dcir here) is a C-type lectin receptor expressed mainly in dendritic cells (DCs) that has a carbohydrate recognition domain in its extracellular portion and an immunoreceptor tyrosine-based inhibitory motif, which transduces negative signals into cells, in its cytoplasmic portion. We found high Dcir expression in the joints of two mouse rheumatoid arthritis models. Because the structural characteristics of Dcir suggest that it may have an immune regulatory role, and because autoimmune-related genes are mapped to the DCIR locus in humans, we generated Dcir-/- mice to learn more about the pathological roles of this molecule. We found that aged Dcir-/- mice spontaneously develop sialadenitis and enthesitis associated with elevated serum autoantibodies. Dcir-/- mice showed a markedly exacerbated response to collagen-induced arthritis. The DC population was expanded excessively in aged and type II collagen-immunized Dcir-/- mice. Upon treatment with granulocyte-macrophage colony-stimulating factor, Dcir-/- mouse-derived bone marrow cells (BMCs) differentiated into DCs more efficiently than did wild-type BMCs, owing to enhanced signal transducer and activator of transcription-5 phosphorylation. These observations indicate that Dcir is a negative regulator of DC expansion and has a crucial role in maintaining the homeostasis of the immune system.

Association of arthritis with a gene complex encoding C‐type lectin–like receptors

To identify susceptibility genes in a rat model of rheumatoid arthritis (RA) and to determine whether the corresponding human genes are associated with RA. Genes influencing oil-induced arthritis (OIA) were position mapped by comparing the susceptibility of inbred DA rats with that of DA rats carrying alleles derived from the arthritis-resistant PVG strain in chromosomal fragments overlapping the quantitative trait locus Oia2. Sequencing of gene complementary DNA (cDNA) and analysis of gene messenger RNA (mRNA) expression were performed to attempt to clone a causal gene. Associations with human RA were evaluated by genotyping single-nucleotide polymorphisms (SNPs) in the corresponding human genes and by analyzing frequencies of alleles and haplotypes in RA patients and age-, sex-, and area-matched healthy control subjects. Congenic DA rats were resistant to OIA when they carried PVG alleles for the antigen-presenting lectin-like receptor gene complex (APLEC), which encodes immunoregulatory C-type lectin-like receptors. Multiple differences in cDNA sequence and mRNA expression precluded cloning of a single causal gene. Five corresponding human APLEC genes were identified and targeted. The SNP rs1133104 in the dendritic cell immunoreceptor gene (DCIR), and a haplotype including that marker and 4 other SNPs in DCIR and its vicinity showed an indication of allelic association with susceptibility to RA in patients who were negative for antibodies to cyclic citrullinated peptide (anti-CCP), with respective odds ratios of 1.27 (95% confidence interval [95% CI] 1.06-1.52; uncorrected P = 0.0073) and 1.37 (95% CI 1.12-1.67; uncorrected P = 0.0019). Results of permutation testing supported this association of the haplotype with RA. Rat APLEC is associated with susceptibility to polyarthritis, and human APLEC and DCIR may be associated with susceptibility to anti-CCP-negative RA.

Signaling and immune regulatory role of the dendritic cell immunoreceptor (DCIR) family lectins: DCIR, DCAR, dectin-2 and BDCA-2

This review focuses on a distinct family of dendritic cells (DC) expressing C-type lectins that include DC immunoreceptor (DCIR), DC immunoactivating receptor (DCAR), DC-associated C-type lectin (dectin)-2 and blood DC antigen (BDCA)-2. DCIR is a type II C-type lectin expressed on antigen presenting cells and granulocytes and acts as an inhibitory receptor via an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM). In contrast, DCAR has been identified as a molecule that forms a putative pair with DCIR. While both molecules share the highly homologous extracellular lectin domain, DCAR lacks the ITIM in its short cytoplasmic tail and acts as an activating receptor through association with the Fc receptor γ chain. Two other lectins, dectin-2 and BDCA-2, are highly related to DCAR by similarities of their amino acid sequence, molecular structure and chromosomal localization. Although they also lack the ITIM, they are capable of transducing signal to regulate cellular functions positively or negatively. Here we propose to designate these four highly related molecules as the “DCIR family lectins” and discuss their signaling mechanisms, carbohydrate recognition, and other features that contribute to the function of DC to control immunity.

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

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 gamma chain and its stable expression on the cell surface. Furthermore, cross-linking of DCAR in the presence of gamma chain activates calcium mobilization and tyrosine phosphorylation of cellular proteins. These signals are mediated by the immunoreceptor tyrosine-based activating motif (ITAM) of the gamma 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 gamma chain. The identification of this activating immunoreceptor provides an example of signaling via a dendritic cell-expressed C-type lectin receptor.

DCIR Acts as an Inhibitory Receptor Depending on its Immunoreceptor Tyrosine-Based Inhibitory Motif

Major histocompatibility complex class II positive cells, namely dendritic cells, monocytes/macrophages, and B cells, are categorized as antigen-presenting cells. Dendritic cells, so-called professional antigen-presenting cells, use distinct sets of surface receptors before and after maturation: those to capture antigens and those to interact with T cells, respectively. But there remain many surface molecules whose functions are still unknown. In this study, we isolated dendritic cell immunoreceptor from mouse bone-marrow-derived mature dendritic cells. Dendritic cell immunoreceptor is a recently reported C-type lectin receptor characteristic with cytoplasmic immunoreceptor tyrosine-based inhibitory motif. Expression of mouse dendritic cell immunoreceptor mRNA was observed specifically in spleen and lymph node, slightly increased with dendritic cell maturation during in vitro culture of bone marrow cells, and was not detected in cultured natural killer cells. Surface expression of mouse dendritic cell immunoreceptor protein was observed in splenic antigen-presenting cells including B cells, monocytes/macrophages, and dendritic cells, but not in T cells. To reveal the downregulating capacity of dendritic cell immunoreceptor in antigen-presenting cells, the change of B-cell-receptor-mediated signals after coligation with a chimeric Fcgamma receptor IIB containing the cytoplasmic portion of mouse dendritic cell immunoreceptor was examined. As a result, we detected two distinct inhibitory effects of cytoplasmic dendritic cell immunoreceptor minus sign inhibition of B-cell-receptor-mediated Ca2+ mobilization and protein tyrosine phosphorylation minus sign and both of these effects required the tyrosine residue inside the immunoreceptor tyrosine-based inhibitory motif. This report presents immunoreceptor tyrosine-based inhibitory motif-dependent negative regulatory function of dendritic cell immunoreceptors. In conclusion, mouse dendritic cell immunoreceptor expressed on antigen-presenting cells can exert two distinct inhibitory signals depending on its immunoreceptor tyrosine-based inhibitory motif tyrosine residue.

Organization of the mouse macrophage C-type lectin (Mcl) gene and identification of a subgroup of related lectin molecules.

A number of genes encoding C-type lectin molecules have been mapped to the natural killer gene complex (NKC) at the distal region of mouse chromosome 6 and to a syntenic region on human chromosome 12p12-p13. In addition to those receptors which regulate NK cell function, related structures expressed on other cells types have also been localized to this chromosomal region. Among these are a number of recently characterized genes, including macrophage C-type lectin (MCL), macrophage-inducible C-type lectin (Mincle), dendritic cell immunoreceptor (DCIR) and dendritic cell-associated lectin-2 (Dectin-2). The amino acid sequences comprising the single C-type lectin domains of MCL, Mincle, DCIR and Dectin-2 are shown here to be closely related to each other. These molecules show overall similarity to two groups of animal C-type lectins, groups II and V, which demonstrate type II transmembrane topology. In this study, sequence analysis suggests that MCL, Mincle, DCIR and Dectin-2 represent a subset of group II-related C-type lectins which may participate in analogous recognition events on macrophages and dendritic cells. The genomic organization of the MCL gene and the sequence of the promoter region, with putative regulatory elements, were determined from a mouse MCL genomic DNA clone and are described here in detail.

Molecular and genomic characterization of human DLEC, a novel member of the C-type lectin receptor gene family preferentially expressed on monocyte-derived dendritic cells.

We have identified a novel gene encoding a protein designated DLEC (dendritic cell lectin), which is a type II membrane glycoprotein of 213 amino acids and belongs to the human calcium-dependent (C-type) lectin family. The cytoplasmic tail of DLEC lacks consensus signaling motifs and its extracellular region shows a single carbohydrate recognition domain (CRD), closest in homology to the dendritic cell immunoreceptor (DCIR) CRD. The DLEC gene has been localized linked to DCIR on the telomeric region of the NK gene complex. RT-PCR and Northern blot analyses show that DLEC mRNA is preferentially expressed in monocyte-derived dendritic cells.

Cloning, mapping and genomic organization of a fish C-type lectin gene from homozygous clones of rainbow trout ( Oncorhynchus mykiss)

Utilizing a splenic cDNA library and rapid amplification of cDNA 5′ ends (5′-RACE), a C-type lectin gene was cloned from a homozygous cloned rainbow trout. The 1176 bp cDNA contains a 714 bp open reading frame from which a 238-amino-acid (aa) (27 kDa) protein was deduced. It was confirmed that this protein belongs to the C-type animal lectins, and is a type II membrane receptor. The predicted protein from this sequence contains a 48 aa cytoplasmic domain, a 20 aa transmembrane domain (TM), a 46 aa stalk region and a 124 aa carbohydrate-recognition domain (CRD). The stalk region contains a leucine-zipper, and an N-glycosylation site was also found in the CRD. Sequence alignment and phylogenetic analysis of the CRD indicate that the protein has similarity with human dendritic cell immunoreceptor (DCIR), gp120 binding C-type lectin (gp120BCL) and mammalian hepatic lectins. The N-terminus (aa 4–183) has similarity with NKG2, a group of C-type lectin receptors important in human natural killer cell function. The genomic DNA (gDNA) containing this gene was amplified and sequenced. The 4569 bp gDNA contains five exons and four introns. The first three exons encode the cytoplasmic domain, the TM and stalk region, respectively. Unlike the other type II C-type lectin receptors in which the CRD was encoded by three exons, the CRD of this lectin was encoded by two exons. A transposon Tc1-like fragment was found in intron III. Intron IV is composed of a simple repeat. Tissue-specific expression of the gene was studied by RT–PCR, and it was mainly expressed in spleen and peripheral blood leukocyte (PBL). Using AluI to digest the fragment containing exon I, intron I and exon II, an RFLP was produced between the sequences of this gene in two cloned fish, OSU 142 and Arlee (AR). Seventy-one doubled haploids (DH) of OSU X AR were screened, and the gene was mapped to linkage group XIV on the published map (Young et al., Genetics 148 (1998) 839).

APCs Express DCIR, a Novel C-Type Lectin Surface Receptor Containing an Immunoreceptor Tyrosine-Based Inhibitory Motif

We have identified a novel member of the calcium-dependent (C-type) lectin family. This molecule, designated DCIR (for dendritic cell (DC) immunoreceptor), is a type II membrane glycoprotein of 237 aa with a single carbohydrate recognition domain (CRD), closest in homology to those of the macrophage lectin and hepatic asialoglycoprotein receptors. The intracellular domain of DCIR contains a consensus immunoreceptor tyrosine-based inhibitory motif. A mouse cDNA, encoding a homologous protein has been identified. Northern blot analysis showed DCIR mRNA to be predominantly transcribed in hematopoietic tissues. The gene encoding human DCIR was localized to chromosome 12p13, in a region close to the NK gene complex. Unlike members of this complex, DCIR displays a typical lectin CRD rather than an NK cell type extracellular domain, and was expressed on DC, monocytes, macrophages, B lymphocytes, and granulocytes, but not detected on NK and T cells. DCIR was strongly expressed by DC derived from blood monocytes cultured with GM-CSF and IL-4. DCIR was mostly expressed by monocyte-related rather than Langerhans cell related DC obtained from CD34+ progenitor cells. Finally, DCIR expression was down-regulated by signals inducing DC maturation such as CD40 ligand, LPS, or TNF-alpha. Thus, DCIR is differentially expressed on DC depending on their origin and stage of maturation/activation. DCIR represents a novel surface molecule expressed by Ag presenting cells, and of potential importance in regulation of DC function.