C-type lectin receptors on dendritic cells and langerhans cells

Figdor, Carl G.; Kooyk, Yvette van; Adema, Gosse J.

doi:10.1038/nri723

Cited by 748 publications

(650 citation statements)

References 55 publications

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“…Importantly, a group of genes in the lectin-dependent complement pathway and carbohydrate binding receptor genes were up-regulated in the Aire -/-DC samples. Notably, DC express C-type lectins, particularly, but not exclusively the MR, to direct their trafficking towards germinal centers and in blood circulation [59]. Interestingly, MR was up-regulated in Aire-deficient DC (Supplemental Table 1).…”

Section: Discussionmentioning

confidence: 99%

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

et al. 2006

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Patients with autoimmune polyendocrine syndrome type I (APS I)suffer from endocrine and non-endocrine disorders due to mutations in the autoimmune regulator gene (AIRE). Mouse Aire is expressed both in thymic medullary epithelial cells and in peripheral antigen-presenting cells, suggesting a role in both central and peripheral tolerance. We here report that Aire -/-dendritic cells (DC) activate naive T cells more efficiently than do Aire +/+ DC. Expression array analyses of Aire -/-DC revealed differential regulation of 68 transcripts, among which, the vascular cell adhesion molecule-1 (VCAM-1) transcript was up-regulated in Aire -/-DC. Concurrently, the expression of the VCAM-1 protein was up-regulated on both Aire -/-DC and monocytes from APS I patients. Blocking the interaction of VCAM-1 prevented enhanced Aire -/-DC stimulation of T cell hybridomas. We determined an increased number of DC in spleen and lymph nodes and of monocytes in the blood from Aire -/-mice, and an increased number of blood monocytes in APS I patients. Our findings imply a role for Aire in peripheral DC regulation of T cell activation, and suggest that Aire participates in peripheral tolerance.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35240_s.pdf IntroductionInactivation of the autoimmune regulator gene (AIRE) [1][2][3] causes autoimmunity in patients with autoimmune polyendocrine syndrome type I (APS I, APECED, OMIM 240300) and in a gene targeted mouse model [4,5]. APS I is a rare monogenic autosomal recessive disease without HLA association [6,7], which is prevalent in isolated populations [8][9][10]. APS I patients develop a progressive loss of tolerance against self antigens and suffer from multiorgan failures due to the immunological destruction of adrenals, parathyroid glands and b cells of the islets of Langerhans [11]. Many of the APS I organ-specific autoantigens have been identified and characterized [12,13]. In addition, as a sign of immune dysfunction, these patients have difficulties clearing Candida albicans infections in mucosal membranes [14]. Functional studies of AIRE suggest a role as a transcription factor and in vitro transactivating studies support this notion [15][16][17][18]. Moreover, the PHD1 domain of AIRE has been suggested to have an E3 ubiquitin ligase activity in cell-free assays [19], findings in variance with a recent report [20]. Aire is highly expressed in a subset of the medullary thymic epithelial cells (mTEC) as well as in DC in the spleen and lymph nodes [21][22][23][24], indicating a potential role in immunological tolerance.To characterize the function of Aire, we previously engineered an Aire-deficient mouse targeting the most common APS I mutation [4]. Aire-deficient mice develop multiple organ-specific autoantibodies and lymphocytic infiltrates, thus mimicking some of the features of human APS I [4]. Subsequently, the role of Aire in negative selection was demonstrated [5]. These findings were further supported using TCR transgenic mic...

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Section: Discussionmentioning

confidence: 99%

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

et al. 2006

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“…The system consists of germline-encoded genes, i.e. toll-like receptors (TLRs) [2], complements [3] and lectins [4], which are pattern recognition receptors (PRRs) that discriminate self from pathogen-associated molecular patterns [5]. Dendritic cells (DCs) and macrophages (Mf) express a variety of PRRs that play important roles in both the innate and adaptive immune responses.…”

Section: Introductionmentioning

confidence: 99%

“…Recent reports revealed that TLRs on DCs and Mf are involved in sensing various components of pathogens [2], giving rise to cellular inflammatory reactions. C-type lectin receptors (CLRs) on DCs and Mf also sense pathogens [4]. CLRs interact with various kinds of pathogens via carbohydrate recognition domains (CRD), which lead to internalization, degradation and subsequent antigen presentation.…”

Section: Introductionmentioning

confidence: 99%

C‐type lectin SIGNR1 enhances cellular oxidative burst response against C. albicans in cooperation with Dectin‐1

et al. 2011

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We investigated the role of SIGNR1 in the recognition of Candida albicans and the subsequent cellular oxidative burst response. Soluble SIGNR1 (sSIGNR1) tetramer bound equally to zymosan and both heat-killed (HK) and live C. albicans in an EDTA-sensitive manner, whereas sDectin-1 tetramer predominantly bound to zymosan and HK-microbes in an EDTA-independent manner. In cellular response, enhanced oxidative burst was observed in RAW264.7 cells expressing SIGNR1 (RAW-SIGNR1) compared with RAW-control cells upon stimulation with HK-C. albicans and zymosan. This response was independent of TLR2 and the cytosolic portion of SIGNR1 but dependent on the recognition by SIGNR1 via carbohydrate recognition domain. Antagonistic laminarin and anti-Dectin-1 mAb cooperatively reduced the response with mannan and anti-SIGNR1 mAb, respectively, although they had no effect by themselves. Moreover, oxidative response and bactericidal activity largely relied on Syk-mediated signaling. RAW-SIGNR1 cells not only captured microbes more efficiently but also showed higher responses than RAW-control cells. Similar enhanced responses were observed in SIGNR-1-expressing resident peritoneal M/. Interestingly, Dectin-1 was recruited to the phagosomal membrane upon the stimulation and physically associated with SIGNR1. These results suggest that SIGNR1 plays a significant role in inducing oxidative response to C. albicans by Syk-dependent signaling, possibly through Dectin-1.Key words: C. albicans . Dectin-1 . Macrophages . SIGNR1 . TLR2 IntroductionInnate immunity is a crucial host defense system that eliminates pathogens as they initiate an infection and leads to the subsequent initiation of the adaptive immune response [1]. The system consists of germline-encoded genes, i.e. toll-like receptors (TLRs) [2] [8][9][10][11][12]. Microbe-mediated stimulation of Dectin-1 results in cellular oxidative burst and cytokine production through its ITAM and the Syk kinase pathway [13,14]. In addition, Dectin-1 has been shown to function collaboratively with TLR2 to stimulate cytokine production [15] and Th17/Treg induction [16].hDC-SIGN recognizes mannose and fucose moieties in the surface of a variety of microbes and viruses, such as Mycobacteria, Leishmania, Salmonella, Candida species, HIV, HCV, dengue virus, CMV, Ebola virus and Sindbis virus (refer to [17]). However, pathogens, i.e. HIV and HCV, have also found ways to subvert and use hDC-SIGN to their advantage [18,19]. Mycobacterium tuberculosis and HIV also target hDC-SIGN in order to upregulate DC production of the immunosuppressive cytokine IL-10 through Raf-1 kinase activation, which induces acetylation of the NF-kB p65 subunit in the presence of co-signaling from TLR4 [20].Mice have eight hDC-SIGN homologues [21,22]. One of these homologues, SIGNR1, has been shown to be expressed on particular Mf subsets in the marginal zone of the spleen, medulla of the lymph nodes and the peritoneal cavity [23][24][25] and to possess mannosebinding activities like hDC-SIGN. SIGNR1 recognizes not only vari...

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“…These proteins are type-II C-type lectin receptors with roles as cell-adhesion receptors and in innate immunity as pathogen receptors. [2][3][4] DC-SIGN and L-SIGN recognize a vast range of bacteria, mycobacteria, viruses and protozoa (reviewed in Koppel et al 2 ). Their function depends on a carbohydrate-recognition domain separated from a transmembrane region by a neck region made up of several 23-amino acid repeats.…”

Section: Introductionmentioning

confidence: 99%

The evolutionary history of the CD209 (DC-SIGN) family in humans and non-human primates

et al. 2008

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The CD209 gene family that encodes C-type lectins in primates includes CD209 (DC-SIGN), CD209L (L-SIGN) and CD209L2. Understanding the evolution of these genes can help understand the duplication events generating this family, the process leading to the repeated neck region and identify protein domains under selective pressure. We compiled sequences from 14 primates representing 40 million years of evolution and from three non-primate mammal species. Phylogenetic analyses used Bayesian inference, and nucleotide substitutional patterns were assessed by codon-based maximum likelihood. Analyses suggest that CD209 genes emerged from a first duplication event in the common ancestor of anthropoids, yielding CD209L2 and an ancestral CD209 gene, which, in turn, duplicated in the common Old World primate ancestor, giving rise to CD209L and CD209. K A /K S values averaged over the entire tree were 0.43 (CD209), 0.52 (CD209L) and 0.35 (CD209L2), consistent with overall signatures of purifying selection. We also assessed the Toll-like receptor (TLR) gene family, which shares with CD209 genes a common profile of evolutionary constraint. The general feature of purifying selection of CD209 genes, despite an apparent redundancy (gene absence and gene loss), may reflect the need to faithfully recognize a multiplicity of pathogen motifs, commensals and a number of self-antigens.

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C-type lectin receptors on dendritic cells and langerhans cells

Cited by 748 publications

References 55 publications

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

C‐type lectin SIGNR1 enhances cellular oxidative burst response against C. albicans in cooperation with Dectin‐1

The evolutionary history of the CD209 (DC-SIGN) family in humans and non-human primates

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