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Siamon Gordon - One of the best experts on this subject based on the ideXlab platform.
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the Mannose Receptor mediates dengue virus infection of macrophages
PLOS Pathogens, 2008Co-Authors: Joanna L. Miller, Luisa Martinezpomares, Barend J M Dewet, Catherine M Radcliffe, Raymond A Dwek, Pauline M Rudd, Siamon GordonAbstract:Macrophages (MO) and mononuclear phagocytes are major targets of infection by dengue virus (DV), a mosquito-borne flavivirus that can cause haemorrhagic fever in humans. To our knowledge, we show for the first time that the MO Mannose Receptor (MR) binds to all four serotypes of DV and specifically to the envelope glycoprotein. Glycan analysis, ELISA, and blot overlay assays demonstrate that MR binds via its carbohydrate recognition domains to mosquito and human cell–produced DV antigen. This binding is abrogated by deglycosylation of the DV envelope glycoprotein. Surface expression of recombinant MR on NIH3T3 cells confers DV binding. Furthermore, DV infection of primary human MO can be blocked by anti-MR antibodies. MR is a prototypic marker of alternatively activated MO, and pre-treatment of human monocytes or MO with type 2 cytokines (IL-4 or IL-13) enhances their susceptibility to productive DV infection. Our findings indicate a new functional role for the MR in DV infection.
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structural model for the Mannose Receptor family uncovered by electron microscopy of endo180 and the Mannose Receptor
Journal of Biological Chemistry, 2006Co-Authors: Jasminka Boskovic, Clare M Isacke, Luisa Martinezpomares, Siamon Gordon, James N Arnold, Richard Stilion, Angel Riveracalzada, Dirk Wienke, Oscar LlorcaAbstract:Abstract The Mannose Receptor family comprises four members in mammals, Endo180 (CD280), DEC-205 (CD205), phospholipase A2 Receptor (PLA2R) and the Mannose Receptor (MR, CD206), whose extracellular portion contains a similar domain arrangement: an N-terminal cysteine-rich domain (CysR) followed by a single fibronectin type II domain (FNII) and 8–10 C-type lectin-like domains (CTLDs). These proteins mediate diverse functions ranging from extracellular matrix turnover through collagen uptake to homeostasis and immunity based on sugar recognition. Endo180 and the MR are multivalent transmembrane Receptors capable of interacting with multiple ligands; in both Receptors FNII recognizes collagens, and a single CTLD retains lectin activity (CTLD2 in Endo180 and CTLD4 in MR). It is expected that the overall conformation of these multivalent molecules would deeply influence their function as the availability of their binding sites could be altered under different conditions. However, conflicting reports have been published on the three-dimensional arrangement of these Receptors. Here, we have used single particle electron microscopy to elucidate the three-dimensional organization of the MR and Endo180. Strikingly, we have found that both Receptors display distinct three-dimensional structures, which are, however, conceptually very similar: a bent and compact conformation built upon interactions of the CysR domain and the lone functional CTLD. Biochemical and electron microscopy experiments indicate that, under a low pH mimicking the endosomal environment, both MR and Endo180 experience large conformational changes. We propose a structural model for the Mannose Receptor family where at least two conformations exist that may serve to regulate differences in ligand selectivity.
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the Mannose Receptor linking homeostasis and immunity through sugar recognition
Trends in Immunology, 2005Co-Authors: Philip R Taylor, Siamon Gordon, Luisa MartinezpomaresAbstract:The Mannose Receptor (MR) can potentially internalize compounds that are recognized by three binding sites located in its extracellular region. It is subject to proteolytic processing and glycosylation, has a complex expression pattern and exhibits tissue-dependent binding properties. It is not surprising, given this complexity, that the MR has been implicated in homeostatic processes, such as clearance of endogenous products and cell adhesion, as well as pathogen recognition and antigen presentation. In this Review, we summarize the current knowledge regarding the different aspects of MR binding properties, contribution to homeostatic clearance, cell activation and antigen presentation.
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recognition of bacterial capsular polysaccharides and lipopolysaccharides by the macrophage Mannose Receptor
Journal of Biological Chemistry, 2002Co-Authors: Susanne Zamze, Luisa Martinezpomares, Hannah Jones, Philip R Taylor, Richard J Stillion, Siamon Gordon, Simon Y C WongAbstract:Abstract The in vitro binding of the macrophage Mannose Receptor to a range of different bacterial polysaccharides was investigated. The Receptor was shown to bind to purified capsular polysaccharides from Streptococcus pneumoniae and to the lipopolysaccharides, but not capsular polysaccharides, from Klebsiella pneumoniae. Binding was Ca2+-dependent and inhibitable withd-Mannose. A fusion protein of the Mannose Receptor containing carbohydrate recognition domains 4–7 and a full-length soluble form of the Mannose Receptor containing all domains external to the transmembrane region both displayed very similar binding specificities toward bacterial polysaccharides, suggesting that domains 4–7 are sufficient for recognition of these structures. Surprisingly, no direct correlation could be made between polysaccharide structure and binding to the Mannose Receptor, suggesting that polysaccharide conformation may play an important role in recognition. The full-length soluble form of the Mannose Receptor was able to bind simultaneously both polysaccharide via the carbohydrate recognition domains and sulfated oligosaccharide via the cysteine-rich domain. The possible involvement of the Mannose Receptor, either cell surface or soluble, in the innate and adaptive immune responses to bacterial polysaccharides is discussed.
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Potential role of the Mannose Receptor in antigen transport.
Immunology Letters, 1999Co-Authors: Luisa Martinez-pomares, Siamon GordonAbstract:Potential endogenous ligands for the cysteine rich domain of the murine Mannose Receptor (MR) have been detected in marginal zone metallophilic macrophages in spleen and subcapsular sinus macrophages in lymph nodes of naive mice by immunohistochemistry using a Fc chimeric protein. Additional labelling was observed in follicular dendritic cells and migratory dendritic cells in immunised animals. Based on this labelling pattern and the identification of a soluble form of the MR in macrophage-conditioned media and mouse serum, we propose a novel role for this Receptor in antigen transport.
R A B Ezekowitz - One of the best experts on this subject based on the ideXlab platform.
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Reduced binding and phagocytosis of Pneumocystis carinii by alveolar macrophages from persons infected with HIV-1 correlates with Mannose Receptor downregulation.
Journal of Clinical Investigation, 1998Co-Authors: Henry Koziel, Martine Y K Armstrong, Frank F Richards, Richard M Rose, B. A. Kruskal, Q. Eichbaum, Paula Pinkston, R. A. Rogers, R A B EzekowitzAbstract:The macrophage Mannose Receptor, a pattern recognition molecule and component of innate immunity, mediates binding and phagocytosis of Pneumocystis carinii and likely represents an important clearance mechanism in the lungs of immunocompetent hosts. The purpose of this study was to examine the ability of alveolar macrophages from HIV-infected individuals to bind and phagocytose P. carinii, and to investigate the role of the macrophage Mannose Receptor in mediating this interaction. Compared with healthy individuals, alveolar macrophage phagocytosis of P. carinii from HIV+ persons was reduced up to 74% (P = 0.02), primarily reflecting a reduction in the number of organisms associated with each macrophage (P = 0.019). Furthermore, macrophages from HIV+ individuals demonstrated up to an 80% (P < 0.05) reduction in Mannose Receptor surface expression and endocytosis. Mannose Receptor affinity was unaltered, and mRNA levels were modestly reduced (P < 0.05). Cells from HIV+ individuals with CD4(+) counts < 200 cells/mm3 (representing individuals at high clinical risk for P. carinii pneumonia) demonstrated the lowest levels of P. carinii phagocytosis and Mannose Receptor endocytosis. In vitro HIV infection of alveolar macrophages from healthy individuals reduced Mannose Receptor endocytosis to 53.2% (P < 0.05) and P. carinii binding and phagocytosis to 67.4% (P < 0.05) of control. Our studies suggest that HIV infection may alter innate immunity in the lungs, and that impaired alveolar macrophage Mannose Receptor-mediated binding and phagocytosis of P. carinii may contribute to the susceptibility of HIV-infected individuals to this opportunistic pulmonary pathogen.
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TH1 AND TH2 CYTOKINES COOPERATE TO STIMULATE Mannose-Receptor-MEDIATED PHAGOCYTOSIS
Journal of Leukocyte Biology, 1998Co-Authors: D. Raveh, B. A. Kruskal, J. Farland, R A B EzekowitzAbstract:The Mannose Receptor is a macrophage surface Receptor that mediates both endocytosis and phagocytosis. Previous work has demonstrated that the prototypical Th2 cytokine, interleukin-4 (IL-4), increases both cell-surface Receptor expres- sion and Mannose Receptor-mediated endocytosis, whereas the prototypical Th1 cytokine, inter- feron-g (IFN-g), decreases both surface expression and endocytosis. In many aspects of the immune response, Th1 and Th2 cytokines oppose each others' actions. We demonstrate that IL-4 and IFN-g alone and together enhance Mannose recep- tor-mediated phagocytosis, despite opposing ef- fects on cell-surface Mannose Receptor expression and endocytosis. Thus these usually antagonistic cytokines cooperate in increasing Mannose recep- tor phagocytic function. The cooperative effect of these cytokines is not observed for Fc Receptor- mediated phagocytosis. The Th2 cytokine IL-13 exerts similar effects to IL-4. Our results suggest that Th1 and Th2 cytokines may act in concert at sites of inflammation to enhance Mannose Receptor- mediated phagocytosis of microorganisms. J. Leu- koc. Biol. 64: 108-113; 1998.
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uptake of pneumocystis carinii mediated by the macrophage Mannose Receptor
Nature, 1991Co-Authors: R A B Ezekowitz, D J Williams, Henry Koziel, Martine Y K Armstrong, A Warner, Frank F Richards, Richard M RoseAbstract:HUMAN exposure to Pneumocystis carinii is common1,2 but, in the absence of acquired3 or genetic4 dysfunction of either cellular or humoral immunity, exposure rarely leads to illness. Although alveolar macrophages can degrade P. carinii5,6, macrophage Receptors involved in P. carinii recognition have not been clearly defined. Characterization of a predominant surface glycoprotein of the high Mannose type7,8 led us to investigate the role of the macrophage Mannose Receptor in this process. We report here that binding and uptake of cultured rat P. carinii by human and rat alveolar macrophages is reduced by 90% in the presence of competitive inhibitors of Mannose Receptor activity and by adherence of alveolar macrophages to mannan-coated surfaces. Further, only those COS cells transfected with the human macrophage Mannose Receptor complementary DNA that express surface Mannose Receptors bind and ingest P. carinii. These studies establish that the macrophage Mannose Receptor is sufficient for uptake of P. carinii and emphasize the role of the alveolar macrophage in first-line host defence against P. carinii.
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molecular characterization of the human macrophage Mannose Receptor demonstration of multiple carbohydrate recognition like domains and phagocytosis of yeasts in cos 1 cells
Journal of Experimental Medicine, 1990Co-Authors: R A B Ezekowitz, K Sastry, P Bailly, A WarnerAbstract:The macrophage Mannose Receptor is an integral membrane protein expressed on the surface of tissue macrophages. After ligation of Mannose-rich glycoconjugates or pathogens, the Receptor mediates endocytosis and phagocytosis of the bound ligands by macrophages. The cDNA-derived primary structure of the Mannose Receptor predicts a cysteine-rich NH2-terminal domain, followed by a fibronectin type II region. The remainder of the ectodomain is comprised of eight carbohydrate recognition-like domains, followed by a transmembrane region, and a cytoplasmic tail. Transfection of the Mannose Receptor cDNA into Cos-I cells is necessary for Receptor-mediated endocytosis of Mannose-rich glycoconjugate as well as phagocytosis of yeasts. Deletion of the cytoplasmic tail results in a mutant Receptor that is able to bind but not ingest the ligated pathogens, suggesting that the signal for phagocytosis is contained in the cytoplasmic tail.
Virginia L. Shepherd - One of the best experts on this subject based on the ideXlab platform.
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Characterization of functional Mannose Receptor in a continuous hybridoma cell line
BMC Immunology, 2012Co-Authors: David J. Vigerust, Sherell Vick, Virginia L. ShepherdAbstract:Background The Mannose Receptor is the best described member of the type I transmembrane C-type lectins; however much remains unanswered about the biology of the Receptor. One difficulty has been the inability to consistently express high levels of a functional full length Mannose Receptor cDNA in mammalian cells. Another difficulty has been the lack of a human macrophage cell line expressing a fully functional Receptor. Commonly used human macrophage cell lines such as U937, THP-1, Mono-Mac and HL60 do not express the Mannose Receptor. We have developed a macrophage hybridoma cell line (43MR cells) created by fusion of U937 cells with primary human monocyte-derived macrophages, resulting in a non-adherent cell line expressing several properties of primary macrophages. The purpose of this study was to identify and select Mannose Receptor-expressing cells using fluorescence-activated cell sorting and to characterize the expression and function of the Receptor.
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IL-4 modulates transcriptional control of the Mannose Receptor in mouse FSDC dendritic cells.
Archives of Biochemistry and Biophysics, 2004Co-Authors: Brian S. Egan, Rasul Abdolrasulnia, Virginia L. ShepherdAbstract:Abstract The Mannose Receptor is a 175 kDa protein found on the surface of macrophages and dendritic cells whose functions include clearance of extracellular hydrolases, internalization of pathogens, and antigen capture. Receptor expression is closely linked to the functional state of these cells and is regulated by cytokines. Previous work has shown that treatment of macrophages and dendritic cells with interleukin-4 leads to increased Mannose Receptor expression. We have examined the mechanism of this IL-4-mediated up-regulation in the murine dendritic cell line FSDC. IL-4 increased Mannose Receptor activity, protein, and mRNA. The Mannose Receptor promoter was functional in FSDCs using transient transfection assays, and IL-4 treatment increased promoter activity 2.6-fold. The responsive region was localized to the proximal 228 bp. Electrophoretic mobility shift assays detected an IL-4-inducible protein that bound to the Mannose Receptor promoter at a site spanning the region between −147 and −108 bp. The sequence TTAC(N)4CACC (−135 and −124 bp) is similar to the IL-4 response region in the Fce Receptor II. Mutation of the flanking TT and CC in this motif blocked IL-4 responsiveness and binding of the IL-4-induced Mannose Receptor binding protein. This protein does not appear to be STAT6 since neither an anti-STAT6 antibody nor a STAT6 consensus oligonucleotide altered factor binding.
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Transcription of a single Mannose Receptor gene by macrophage and retinal pigment epithelium
Ophthalmic Research, 2003Co-Authors: Cynthia J. Greaton, Kirk B. Lane, Virginia L. Shepherd, Barbara J. MclaughlinAbstract:To determine if the macrophage Mannose Receptor transcript is present in mouse, rat, pig, and human retinal pigment epithelium (RPE), primary cultures and/or freshly dissected retinal pigment epithelium from four different species were used to isolate total RNA. RT-PCR was used to amplify segments of the macrophage Mannose Receptor from each sample. Amplified products were sequenced and compared with known sequences of the macrophage Mannose Receptor. Macrophage Mannose Receptor transcripts were identified in all RPE samples. Comparison between sequences identified in RPE with macrophage sequences from the same species revealed 100% identity. Sequence homology between the different species was 74% or greater. These data are consistent with the transcription of a single Mannose Receptor gene by these two phagocytic cell types.
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HIV-1 Tat Represses Transcription from the Mannose Receptor Promoter
Journal of Immunology, 2000Co-Authors: Robert L. Caldwell, Brian S. Egan, Virginia L. ShepherdAbstract:The Mannose Receptor is expressed on mature macrophages and immature dendritic cells, and functions to mediate phagocytosis of pathogens and capture of Ags for delivery to MHC class II-containing intracellular compartments. It has been previously reported that HIV-1-infected macrophages have reduced functions associated with the Mannose Receptor, including impaired Pneumocystis carinii phagocytosis and mannosylated albumin uptake. Several HIV-1-derived proteins including the Tat protein have been shown to transcriptionally repress host cell genes. The present study was undertaken to define the role of the HIV-1-derived protein Tat in HIV-mediated Mannose Receptor down-regulation. Cotransfection of the human macrophage cell line U937 with a Tat expression vector and a Mannose Receptor promoter-luciferase reporter construct resulted in down-regulation of Mannose Receptor promoter activity. This repression was targeted to the basal promoter. Expression of either one- or two-exon Tat resulted in decreased promoter activity. The addition of the transactivation response element (TAR) sequence enhanced the Tat-mediated repression. Down-regulation was also seen when transfected cells were treated with exogenously added Tat protein. These results are consistent with a mechanism whereby Tat reduces Mannose Receptor promoter activity by interfering with the host transcriptional initiation machinery, potentially resulting in decreased levels of surface Mannose Receptor available for Ag or pathogen capture.
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PU.1 and USF Are Required for Macrophage-specific Mannose Receptor Promoter Activity
Journal of Biological Chemistry, 1999Co-Authors: Brian S. Egan, Kirk B. Lane, Virginia L. ShepherdAbstract:Abstract In the current study we report the isolation of 854 base pairs of the rat Mannose Receptor promoter. Analysis of the sequence revealed one Sp1 site, three PU.1 sites, and a potential TATA box (TTTAAA) 33 base pairs 5′ of the transcriptional start site. The tissue specificity of the promoter was determined using transient transfections. The promoter was most active in the mature macrophage cell line NR8383 although the promoter also showed activity in the monocytic cell line RAW. No activity was observed in pre-monocytic cell lines or epithelial cell lines. Mutation of the TTTAAA sequence to TTGGAA resulted in a 50% decrease in activity in transient transfection assays suggesting that the promoter contains a functional TATA box. Using electrophoretic mobility shift assays and mutagenesis we established that the transcription factors Sp1, PU.1, and USF bound to the Mannose Receptor promoter, but only PU.1 and USF contributed to activation. Transient transfections using a dominant negative construct of USF resulted in a 50% decrease in Mannose Receptor promoter activity, further establishing the role of USF in activating the rat Mannose Receptor promoter. Comparison of the rat, mouse, and human sequence demonstrated that some binding sites are not conserved. Gel shifts were performed to investigate differences in protein binding between species. USF bound to the rat and human promoter but not to the mouse promoter, suggesting that different mechanisms are involved in regulation of Mannose Receptor expression in these species. From these results we conclude that, similar to other myeloid promoters, transcription of the rat Mannose Receptor is regulated by binding of PU.1 and a ubiquitous factor at an adjacent site. However, unlike other myeloid promoters, we have identified USF as the ubiquitous factor, and demonstrated that the promoter contains a functional TATA box.
Philip D. Stahl - One of the best experts on this subject based on the ideXlab platform.
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The Macrophage Mannose Receptor and Innate Immunity
2003Co-Authors: Thiruvamoor P. Ramkumar, Djilali Hammache, Philip D. StahlAbstract:Multilectin Receptors, as the name implies, have multiple lectin domains present within a single peptide backbone. There are four known members in this class of molecules, the best studied of which is the macrophage Mannose Receptor (MR). This chapter discusses the structure and function of the multilectin Receptors as represented by the macrophage MR and its proposed role in the innate immune response (for recent review articles on the Mannose Receptor, see refs. 1–3).
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Identification and functional characterization of the Mannose Receptor in astrocytes
Glia, 1999Co-Authors: E.m.e. Burudi, Philip D. Stahl, Sigrid Riese, Anne Régnier-vigourouxAbstract:The immune competence of astrocytes is still ill defined, especially their endocytic capacity, a prerequisite for efficient antigen presentation. We show that Mannose Receptor, a very important conduit for internalization of infectious agents and self antigens, is functionally expressed in the murine CNS. By in vitro assays, astrocytes and microglia were shown to be the prime cells expressing this Receptor. Studies on astrocytes demonstrate that its expression and function are inversely regulated by anti- and pro-inflammatory compounds. Downregulation of the Mannose Receptor by IFN-γ is concomitant with the induction of the invariant chain, which is also induced by GM-CSF + IL-4. Mannose Receptor-expressing astrocytes may thus act as scavenger not only in CNS development but also in defense, against soluble and particulate mannosylated pathogens, presenting fragments thereof at strategic locations in the CNS. These findings unravel a new and putatively very important role of astrocytes in innate immunity and possibly development. GLIA 25:44–55, 1999. © 1999 Wiley-Liss, Inc.
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A Functional Soluble Form of the Murine Mannose Receptor Is Produced by Macrophages in Vitro and Is Present in Mouse Serum
Journal of Biological Chemistry, 1998Co-Authors: Luisa Martinez-pomares, Philip D. Stahl, James A. Mahoney, Rita Káposzta, Sheena A. Linehan, Siamon GordonAbstract:Abstract A soluble form of the Mannose Receptor (sMR) has been found in conditioned medium of primary macrophages in vitro and in mouse serum. sMR was released as a single species, had a smaller size than the cell-associated form, and accumulated in macrophage-conditioned medium, in a cytokine-regulated manner, to levels comparable with those found for cell-associated Mannose Receptor. Pulse-chase experiments showed that sMR production in culture occurred by constitutive cleavage of pre-existing full-length protein. A binding assay was developed to determine the sugar specificity of sMR and its ability to interact with pathogens and particulate antigens (i.e. Candida albicans and zymosan). Protease inhibitor studies suggested that sMR was produced by cleavage of an intact Mannose Receptor by a matrix metalloprotease or ADAM metalloprotease. A role for sMR in the immune response is proposed based on its binding properties, regulation by cytokines, and the previous discovery of putative ligands for the cysteine-rich domain of the Mannose Receptor in lymph nodes and spleen.
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REGULATION OF Mannose Receptor SYNTHESIS AND TURNOVER IN MOUSE J774 MACROPHAGES
Journal of Leukocyte Biology, 1998Co-Authors: Maria L. Fiani, Jill Beitz, Diane N. Turvy, Janice S. Blum, Philip D. StahlAbstract:The Mannose Receptor, present on the plasma membrane of macrophages, promotes the internalization of glycoproteins and glycoconju- gates via both endocytic and phagocytic pathways. The expression of this Receptor is tightly modulated during monocyte/Mf differentiation and cellular activation. We isolated clonal populations from murine J774 macrophage tumor cells, which differ in their surface expression of functional Mannose Receptors. To examine the potential mechanisms regulating Receptor function in these cell lines, the interaction of Receptor with ligand as well as recep- tor synthesis and degradation was analyzed. J774 clones with both high and low levels of Mannose Receptor activity were found to synthesize signifi- cant amounts of Receptor protein, suggesting that the protein may be regulated at the level of synthe- sis and degradation. In J774 clones expressing very low Receptor activity and protein, the half-life of Mannose Receptor molecules was substantially de- creased. The evolution of multiple mechanisms modulating Mannose Receptor function may be critical in fine-tuning the role of this Receptor in antigen processing and in scavenger and host de- fense functions. J. Leukoc. Biol. 64: 85-91; 1998.
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the Mannose Receptor is a pattern recognition Receptor involved in host defense
Current Opinion in Immunology, 1998Co-Authors: Philip D. Stahl, Alan R B EzekowitzAbstract:Abstract The Mannose Receptor recognizes the patterns of carbohydrates that decorate the surfaces and cell walls of infectious agents. This macrophage and dendritic cell pattern-recognition Receptor mediates endocytosis and phagocytosis. The Mannose Receptor is the prototype of a new family of multilectin Receptor proteins (membrane-spanning Receptors containing eight-ten lectin-like domains, which appear to play a key role in host defense) and provides a link between innate and adaptive immunity. Recent advances include the identification of three new members of the Mannose Receptor family, additional work on defining the molecular requirements for sugar binding, a role for the Mannose Receptor in antigen presentation of lipoglycan antigens and evidence that the Mannose Receptor is associated with a signal transduction pathway leading to cytokine production
Angus W Thomson - One of the best experts on this subject based on the ideXlab platform.
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rapamycin inhibits macropinocytosis and Mannose Receptor mediated endocytosis by bone marrow derived dendritic cells
Blood, 2002Co-Authors: Holger Hackstein, Timucin Taner, Alison J Logar, Angus W ThomsonAbstract:Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that use 2 major pathways for antigen uptake: constitutive macropinocytosis and Mannose Receptor–mediated endocytosis. Efficient endocytosis is critical for DCs to fulfill their sentinel function in immunity. We investigated the influence of the immunosuppressive macrolide rapamycin on macropinocytosis of fluorescein isothiocyanate (FITC)–albumin and Mannose Receptor–mediated endocytosis of FITC-dextran by murine bone marrow–derived DCs by flow cytometry. The data show that (1) at a low, physiologically relevant concentration (1 ng/mL), rapamycin impairs macropinocytosis and Mannose Receptor–mediated endocytosis; (2) the effects are independent of DC maturation and can be demonstrated specifically in immature CD11c+ major histocompatibility complex (MHC) class IIlo DCs by 3-color flow cytometry; (3) inhibition of endocytosis is not related to apoptotic cell death; and (4) molar excess of the structurally related molecule FK506 inhibits the actions of rapamycin. The inhibitory effects of rapamycin on DC endocytosis were confirmed in vivo. To our knowledge, this is the first report that a clinically relevant immunosuppressant inhibits DC endocytosis.