The Mannose Receptor Mediates Uptake of Soluble but Not of Cell-Associated Antigen for Cross-Presentation

Institute of Molecular Medicine and Experimental Immunology (IMMEI), Friedrich-Wilhelms-Universität, Bonn, Germany.
The Journal of Immunology (Impact Factor: 4.92). 07/2006; 176(11):6770-6. DOI: 10.4049/jimmunol.176.11.6770
Source: PubMed


The mannose receptor (MR) has been implicated in the recognition and clearance of microorganisms and serum glycoproteins. Its endocytic function has been studied extensively using macrophages, although it is expressed by a variety of cell types, including dendritic cells (DC). In this study, we investigated its role in Ag presentation by DC using MR-/- mice. Uptake of the model Ag, soluble OVA, by bone marrow-derived DC and in vitro activation of OVA-specific CD8 T cells (OT-I cells) strictly depended on the MR. In vivo, MR deficiency impaired endocytosis of soluble OVA by DC and concomitant OT-I cell activation. No alterations in the DC subtype composition in MR-/- mice were accountable. Uptake of cell-associated OVA was unaffected by MR deficiency, resulting in unchanged activation of OT-I cells. These findings demonstrate that DC use the MR for endocytosis of a particular Ag type intended for cross-presentation.

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    • "A different approach is the targeting of the internalization system of DCs. In this respect the mannose receptor (MR), an endocytic receptor expressed by dendritic cells that is involved in binding and uptake of carbohydrates and related molecules [15], is of great interest. "
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    ABSTRACT: The use of synthetic long peptides (SLP) has been proven to be a promising approach to induce adaptive immune responses in vaccination strategies. Here, we analyzed whether the efficiency to activate cytotoxic T cells by SLP-based vaccinations can be increased by conjugating SLPs to mannose residues. We could demonstrate that mannosylation of SLPs results in increased internalization by the mannose receptor (MR) on murine antigen-presenting cells. MR-mediated internalization targeted the mannosylated SLPs into early endosomes, from where they were cross-presented very efficiently compared to non-mannosylated SLPs. The influence of SLP mannosylation was specific for cross-presentation, as no influence on MHC II-restricted presentation was observed. Additionally, we showed that vaccination of mice with mannosylated SLPs containing epitopes from either ovalbumin or HPV E7 resulted in enhanced proliferation and activation of antigen-specific CD8+ T cells. These findings demonstrate that mannosylation of SLPs augments the induction of a cytotoxic T cell response in vitro and in vivo and might be a promising approach to induce cytotoxic T cell responses in e.g. cancer therapy and anti-viral immunity.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "OVA is a phosphorylated glycoprotein having 386 amino acid residues, and a molecular weight of approximately 45 kDa.[15] OVA has several mannose (carbohydrate) residues, which binds to the mannose receptors expressed by antigen presenting cells such as macrophages, dendritic cells (DCs), and monocytes.[1617] Studies have also identified some specific peptides of OVA contains both T and B cell epitopes.[18] "
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    ABSTRACT: Aim: The aim was to investigate the antiallergic effect of an aqueous leaf extract of Pistia stratiotes (ALPS) in a murine model of ovalbumin (OVA)-induced allergic conjunctivitis (AC). Materials and Methods: Prior to topical challenge (instillation of 1.5 mg OVA in 10 μL phosphate buffered saline into their conjunctival sacs) to induce AC, groups of sensitized Imprinting Control Region mice (injected IP, on day 1 and 7, with 0.2 ml solution of 100 μg OVA and 0.01 mg aluminum hydroxide in phosphate buffered saline), were treated with 5 mg/kg cetirizine, 10, 50 or 100 mg/kg of ALPS, or 2 ml/kg normal saline per os. Conjunctival redness, lid edema, tearing and lid scratching (clinical symptoms of AC) were scored. Serum OVA specific immunoglobulins were determined using ELISA. Histopathological assessment of the conjunctival mucosal tissue was conducted. The extract was screened for secondary plant metabolites. Results: Pretreatment with the extract significantly (P ≤ 0.05–0.01) and dose-dependently reduced the scores for clinical symptoms, which were marked in vehicle-pretreated mice. Pretreatment also lowered (P ≤ 0.01–0.001) serum OVA specific immunoglobulins. Mast cell infiltration and degranulation in conjunctival stroma (measured by an inflammatory score) in histopathological studies was also significantly low (P ≤ 0.05–0.01) on pretreatment. Conclusion: The ALPS exhibited interesting antiallergic activity and hence could be useful in managing AC.
    Full-text · Article · Mar 2014 · Pharmacognosy Research
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    • "It has been shown that uptake of OVA by pinocytosis in DCs resulted in the activation of OVA-specific CD4+ T cells, but evoked no CD8+ T cell response [6]. In contrast, endocytotic uptake of OVA, which is efficiently bound by the mannose receptor (MR) due to its mannosylation [7], resulted in strong activation of either T cell population. "
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    ABSTRACT: Dendritic cells (DCs) constitute an attractive target for specific delivery of nanovaccines for immunotherapeutic applications. Here we tested nano-sized dextran (DEX) particles to serve as a DC-addressing nanocarrier platform. Non-functionalized DEX particles had no immunomodulatory effect on bone marrow (BM)-derived murine DCs in vitro. However, when adsorbed with ovalbumine (OVA), DEX particles were efficiently engulfed by BM-DCs in a mannose receptor-dependent manner. A DEX-based nanovaccine containing OVA and lipopolysaccharide (LPS) as a DC stimulus induced strong OVA peptide-specific CD4(+) and CD8(+) T cell proliferation both in vitro and upon systemic application in mice, as well as a robust OVA-specific humoral immune response (IgG1>IgG2a) in vivo. Accordingly, this nanovaccine also raised both a more pronounced delayed-type hypersensitivity response and a stronger induction of cytotoxic CD8(+) T cells than obtained upon administration of OVA and LPS in soluble form. Therefore, DEX-based nanoparticles constitute a potent, versatile and easy to prepare nanovaccine platform for immunotherapeutic approaches.
    Full-text · Article · Dec 2013 · PLoS ONE
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