Zymosan is a β-glucan– and mannan-rich particle that is widely used as a cellular activator for examining the numerous responses effected by phagocytes. The macrophage mannose receptor (MR) and complement receptor 3 (CR3) have historically been considered the major macrophage lectins involved in the nonopsonic recognition of these yeast-derived particles. Using specific carbohydrate inhibitors, we show that a β-glucan receptor, but not the MR, is a predominant receptor involved in this process. Furthermore, nonopsonic zymosan binding was unaffected by genetic CD11b deficiency or a blocking monoclonal antibody (mAb) against CR3, demonstrating that CR3 was not the β-glucan receptor mediating this activity. To address the role of the recently described β-glucan receptor, Dectin-1, we generated a novel anti–Dectin-1 mAb, 2A11. Using this mAb, we show here that Dectin-1 was almost exclusively responsible for the β-glucan–dependent, nonopsonic recognition of zymosan by primary macro-phages. These findings define Dectin-1 as the leukocyte β-glucan receptor, first described over 50 years ago, and resolves the long-standing controversy regarding the identity of this important molecule. Furthermore, these results identify Dectin-1 as a new target for examining the immunomodulatory properties of β-glucans for therapeutic drug design.
We recently identified dectin-1 (βGR) as a major β-glucan receptor on leukocytes and demonstrated that it played a significant role in the non-opsonic recognition of soluble and particulate β-glucans. Using a novel mAb (2A11) raised against βGR, we show here that the receptor is not dendritic cell-restricted as first reported, but is broadly expressed, with highest surface expression on populations of myeloid cells (monocyte/macrophage (Mφ) and neutrophil lineages). Dendritic cells and a subpopulation of T cells also expressed the βGR, but at lower levels. Alveolar Mφ, like inflammatory Mφ, exhibited the highest surface expression of βGR, indicative of a role for this receptor in immune surveillance. In contrast, resident peritoneal Mφ expressed much lower levels of βGR on the cell surface. Characterization of the nonopsonic recognition of zymosan by resident peritoneal Mφ suggested the existence of an additional β-glucan-independent mechanism of zymosan binding that was not observed on elicited or bone marrow-derived Mφ. Although this recognition could be inhibited by mannan, we were able to exclude involvement of the Mφ mannose receptor and complement receptor 3 in this process. These observations imply the existence of an additional mannan-dependent receptor involved in the recognition of zymosan by resident peritoneal Mφ.
Complement is an ancient danger-sensing system that contributes to host defense, immune surveillance and homeostasis. C5a and its G protein–coupled receptor mediate many of the proinflammatory properties of complement. Despite the key role of C5a in allergic asthma, autoimmune arthritis, sepsis and cancer, knowledge about its regulation is limited. Here we demonstrate that IgG1 immune complexes (ICs), the inhibitory IgG receptor FcγRIIB and the C-type lectin–like receptor dectin-1 suppress C5a receptor (C5aR) functions. IgG1 ICs promote the association of FcγRIIB with dectin-1, resulting in phosphorylation of Src homology 2 domain–containing inositol phosphatase (SHIP) downstream of FcγRIIB and spleen tyrosine kinase downstream of dectin-1. This pathway blocks C5aR-mediated ERK1/2 phosphorylation, C5a effector functions in vitro and C5a-dependent inflammatory responses in vivo, including peritonitis and skin blisters in experimental epidermolysis bullosa acquisita. Notably, high galactosylation of IgG N-glycans is crucial for this inhibitory property of IgG1 ICs, as it promotes the association between FcγRIIB and dectin-1. Thus, galactosylated IgG1 and FcγRIIB exert anti-inflammatory properties beyond their impact on activating FcγRs.
The β-glucan receptor Dectin-1 is an archetypical non-toll-like pattern recognition receptor expressed predominantly by myeloid cells, which can induce its own intracellular signalling and can mediate a variety of cellular responses, such as cytokine production. Recent identification of the components of these signalling pathways, such as Syk kinase, CARD9 and Raf-1, has provided novel insights into the molecular mechanisms underlying Dectin-1 function. Furthermore, a broader appreciation of the cellular responses mediated by this receptor and the effects of interactions with other receptors, including the TLRs, have greatly furthered our understanding of innate immunity and how this drives the development of adaptive immunity, particularly Th17 responses. Recent studies have highlighted the importance of Dectin-1 in anti-fungal immunity, in both mice and humans, and have suggested a possible involvement of this receptor in the control of mycobacterial infections.
We identified the C-type-lectin-like receptor, Dectin-1, as the major receptor for fungal b-glucans on murine macrophages and have demonstrated that it plays a significant role in the cellular response to these carbohydrates. Using two novel, isoform-specific mAb, we show here that human Dectin-1, the b-glucan receptor (bGR), is widely expressed and present on all monocyte populations as well as macrophages, DC, neutrophils and eosinophils. This receptor is also expressed on B cells and a subpopulation of T cells, demonstrating that human Dectin-1 is not myeloid restricted. Both major functional bGR isoforms -bGR-A and bGR-B -were expressed by these cell populations in peripheral blood; however, only bGR-B was significantly expressed on mature monocyte-derived macrophages and immature DC, suggesting cell-specific control of isoform expression. Inflammatory cells, recruited in vivo using a new skin-window technique, demonstrated that Dectin-1 expression was not significantly modulated on macrophages during inflammation, but is decreased on recruited granulocytes. Despite previous reports detailing the involvement of other b-glucan receptors on mature human macrophages, we have demonstrated that Dectin-1 acted as the major b-glucan receptor on these cells and contributed to the inflammatory response to these carbohydrates.
Targeting of Ags and therapeutics to dendritic cells (DCs) has immense potential for immunotherapy and vaccination. Because DCs are heterogeneous, optimal targeting strategies will require knowledge about functional specialization among DC subpopulations and identification of molecules for targeting appropriate DCs. We characterized the expression of a fungal recognition receptor, DC-associated C-type lectin-1 (Dectin-1), on mouse DC subpopulations and investigated the ability of an anti-Dectin-1 Ab to deliver Ag for the stimulation of immune responses. Dectin-1 was shown to be expressed on CD8α−CD4−CD11b+ DCs found in spleen and lymph nodes and dermal DCs present in skin and s.c. lymph nodes. Injection of Ag-anti-Dectin-1 conjugates induced CD4+ and CD8+ T cell and Ab responses at low doses where free Ag failed to elicit a response. Notably, qualitatively different immune responses were generated by targeting Ag to Dectin-1 vs CD205, a molecule expressed on CD8α+CD4−CD11b− DCs, dermal DCs, and Langerhans cells. Unlike anti-Dectin-1, anti-CD205 conjugates failed to elicit an Ab response. Moreover, when conjugates were injected i.v., anti-Dectin-1 stimulated a much stronger CD4+ T cell response and a much weaker CD8+ T cell response than anti-CD205. The results reveal Dectin-1 as a potential targeting molecule for immunization and have implications for the specialization of DC subpopulations.
Our resistance to infection is critically dependent upon the ability of pattern recognition receptors to recognise microbial invasion and induce protective immune responses. One such family of receptors are the C-type lectins, which play central roles in antifungal immunity1. These receptors activate key effector mechanisms upon recognition of conserved fungal cell wall carbohydrates. However, several other immunologically active fungal ligands have been described, including melanin2,3, whose mechanisms of recognition remain largely undefined. Here we identify a C-type lectin receptor, Melanin sensing C-type Lectin receptor (MelLec), that plays an essential role in antifungal immunity through recognition of the naphthalene-diol unit of 1,8-dihydroxynaphthalene (DHN)-melanin. MelLec recognises melanin in conidial spores of Aspergillus fumigatus, as well as other DHN-melanised fungi and is ubiquitously expressed by CD31+ endothelial cells in mice. MelLec is also expressed by a sub-population of these cells in mice that co-express EpCAM and which were detected only in the lung and liver. In mouse models, MelLec was required for protection against disseminated infection with A. fumigatus. In humans, MelLec is also expressed by myeloid cells, and we identified a single nucleotide polymorphism of this receptor that negatively affected myeloid inflammatory responses and significantly increased susceptibility of stem-cell transplant recipients to disseminated Aspergillus infections. Thus MelLec is a receptor recognising an immunologically active component commonly found on fungi and plays an essential role in protective antifungal immunity in both mice and humans.
Background: C-type lectins play important roles in immunity and homeostasis.Results: CLECSF8 is expressed on neutrophils and monocytes and can mediate phagocytosis, the respiratory burst and inflammatory cytokine production, in part through association with a novel adaptor.Conclusion: CLECSF8 can trigger cellular activation.Significance: This study identifies a novel C-type lectin that can control immune cell function.
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