Identification of lectin-like receptors expressed by antigen presenting cells and neutrophils and their mapping to a novel gene complex

Abstract

In an experimental rat model, we recently mapped an arthritis susceptibility locus to the distal part of Chromosome 4 containing genes predicted to encode C-type lectin superfamily (CLSF) receptors. Here we report the cDNA cloning and positional arrangement of these receptor genes, which represent rat orthologues to human Mincle and DCIR and to mouse MCL and Dectin-2, as well as four novel receptors DCIR2, DCIR3, DCIR4 and DCAR1, not previously reported in other species. We furthermore report the cDNA cloning of human Dectin-2 and MCL, and of the mouse orthologues to the novel rat receptors. Similar to the killer-cell lectin-like receptors (KLR) some of these receptors exhibit structural features suggesting that they regulate leukocyte reactivity; e.g., human DCIR and rodent DCIR1 and DCIR2 carry an immunoreceptor tyrosine-based inhibitory motif (ITIM), predicting inhibitory function, and conversely, in all three species Mincle has a positively charged amino acid in the transmembrane region, suggesting activating function. Sequence comparisons show that the receptors form a discrete family, more closely related to group II CLSF receptors than to the group V KLR. Their distance to the KLR is underscored by their preservation of evolutionary conserved calcium/saccharide binding residues, present in group II and lacking in group V CLSF and their cellular expression patterns, with most of the genes preferentially expressed by professional antigen-presenting cells (dendritic cells, macrophages and B cells) and neutrophils. In all three species, the genes map together, forming an evolutionary conserved gene complex, which we call the antigen presenting lectin-like receptor complex (APLEC).

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).…”

“…mDCAR1 was identified as one of six CLRs after searching for mouse orthologs of the well-characterized BDCA-2 (CD303) and hDCIR. In accordance to the nomenclature introduced by Bates et al (13) for DCIR and enlarged by Kanazawa et al (21) with the characterization of DCAR, Flornes et al (6) published an expanded analysis of the APLEC and named the resulting mouse receptors DCIR1, DCIR2, DCIR3, DCIR4, DCAR1, and DCAR2. To simplify matters, we renamed DCIR1 DCIR and DCAR2 DCAR, as described by Kanazawa et al (30).…”

“…Data are representative of at least three independent experiments. (5,6,10,30). Several members of the CLR family have been implicated in microbial pattern recognition, Ag uptake and regulation of cell-mediated immune responses (3), whereas others are known only due to their genetic proximity.…”

Heterogeneous but conserved natural killer receptor gene complexes in four major orders of mammals

“…Some of the CLEC genes apparently belong to this category (e.g., CLEC2D genes; ref. 6); several other CLEC genes, however, are expressed in different cell types but not in NK cells (19,20). The CLEC genes lack a positive unifying feature that would distinguish them from the KLR genes; they are defined negatively as NKC genes whose products do not function as NK cell receptors.…”

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

“…5,6 The cluster contains seven genes encoding C-type lectin-like receptors, that is, Mincle, Mcl, Dcar1 and Dcir1-Dcir4, which are expressed on leukocytes, to some extent on T lymphocytes, 7 but mainly on neutrophils and antigen-presenting cells, including macrophages. [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.…”