scholarly journals DC-SIGN Is the Major Mycobacterium tuberculosis Receptor on Human Dendritic Cells

2002 ◽  
Vol 197 (1) ◽  
pp. 121-127 ◽  
Author(s):  
Ludovic Tailleux ◽  
Olivier Schwartz ◽  
Jean-Louis Herrmann ◽  
Elisabeth Pivert ◽  
Mary Jackson ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mycobacterium Tuberculosis ◽  
Human Monocyte ◽  
Mannose Receptor ◽  
Intercellular Adhesion Molecule ◽  
Minor Role ◽  
Hla Dr ◽  
A Minor ◽  
Human Dendritic Cells

Early interactions between lung dendritic cells (LDCs) and Mycobacterium tuberculosis, the etiological agent of tuberculosis, are thought to be critical for mounting a protective anti-mycobacterial immune response and for determining the outcome of infection. However, these interactions are poorly understood, at least at the molecular level. Here we show that M. tuberculosis enters human monocyte-derived DCs after binding to the recently identified lectin DC-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN). By contrast, complement receptor (CR)3 and mannose receptor (MR), which are the main M. tuberculosis receptors on macrophages (Mϕs), appeared to play a minor role, if any, in mycobacterial binding to DCs. The mycobacteria-specific lipoglycan lipoarabinomannan (LAM) was identified as a key ligand of DC-SIGN. Freshly isolated human LDCs were found to express DC-SIGN, and M. tuberculosis–derived material was detected in CD14−HLA-DR+DC-SIGN+ cells in lymph nodes (LNs) from patients with tuberculosis. Thus, as for human immunodeficiency virus (HIV), which is captured by the same receptor, DC-SIGN–mediated entry of M. tuberculosis in DCs in vivo is likely to influence bacterial persistence and host immunity.

scholarly journals AM3 Modulates Dendritic Cell Pathogen Recognition Capabilities by Targeting DC-SIGN

2007 ◽  
Vol 51 (7) ◽  
pp. 2313-2323 ◽  
Author(s):  
Diego Serrano-Gómez ◽  
Rocío T. Martínez-Nuñez ◽  
Elena Sierra-Filardi ◽  
Nuria Izquierdo ◽  
María Colmenares ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Molecular Mechanisms ◽  
Human Monocyte ◽  
Mannose Receptor ◽  
Receptor Expression ◽  
Intercellular Adhesion Molecule ◽  
Dependent Manner ◽  
Pathogen Recognition ◽  
Gp120 Protein ◽  
Human Dendritic Cells

ABSTRACT AM3 (Inmunoferon) is an orally effective immunomodulator that influences the regulatory and effector functions of the immune system whose molecular mechanisms of action are mostly unknown. We hypothesized that the polysaccharide moiety of AM3 (IF-S) might affect immune responses by modulating the lectin-dependent pathogen recognition abilities of human dendritic cells. IF-S inhibited binding of viral, fungal, and parasite pathogens by human monocyte-derived dendritic cells in a dose-dependent manner. IF-S specifically impaired the pathogen recognition capabilities of DC-SIGN, as it reduced the attachment of Candida, Aspergillus, and Leishmania to DC-SIGN transfectants. IF-S also inhibited the interaction of DC-SIGN with both its cellular counterreceptor (intercellular adhesion molecule 3) and the human immunodeficiency virus (HIV) type 1 gp120 protein and blocked the DC-SIGN-dependent capture of HIV virions and the HIV trans-infection capability of DC-SIGN transfectants. IF-S promoted DC-SIGN internalization in DCs without affecting mannose receptor expression, and 1D saturation transfer difference nuclear magnetic resonance demonstrated that IF-S directly interacts with DC-SIGN on the cell surface. Therefore, the polysaccharide moiety of AM3 directly influences pathogen recognition by dendritic cells by interacting with DC-SIGN. Our results indicate that DC-SIGN is the target for an immunomodulator and imply that the adjuvant and immunomodulatory actions of AM3 are mediated, at least in part, by alteration of the DC-SIGN functional activities.

scholarly journals Infection of Human Dendritic Cells with a Mycobacterium tuberculosis sigE Mutant Stimulates Production of High Levels of Interleukin-10 but Low Levels of CXCL10: Impact on the T-Cell Response

2006 ◽  
Vol 74 (6) ◽  
pp. 3296-3304 ◽  
Author(s):  
Elena Giacomini ◽  
Ambar Sotolongo ◽  
Elisabetta Iona ◽  
Martina Severa ◽  
Maria Elena Remoli ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mycobacterium Tuberculosis ◽  
Human Monocyte ◽  
Interleukin 10 ◽  
T Cell Response ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Effector Cells ◽  
Human Dendritic Cells

ABSTRACT The Mycobacterium tuberculosis genome encodes 13 sigma factors. We have previously shown that mutations in some of these transcriptional activators render M. tuberculosis sensitive to various environmental stresses and can attenuate the virulence phenotype. In this work, we focused on extracytoplasmic factor σE and studied the effects induced by the deletion of its structural gene (sigE) in the infection of human monocyte-derived dendritic cells (MDDC). We found that the wild-type M. tuberculosis strain (H37Rv), the sigE mutant (ST28), and the complemented strain (ST29) were able to infect dendritic cells (DC) to similar extents, although at 4 days postinfection a reduced ability to grow inside MDDC was observed for the sigE mutant ST28. After mycobacterium capture, the majority of MDDC underwent full maturation and expressed both inflammatory cytokines, such as tumor necrosis factor alpha, and the regulatory cytokines interleukin-12 (IL-12), IL-18, and beta interferon (IFN-β). Conversely, a higher level of production of IL-10 was observed in ST28-infected MDDC compared to H37Rv- or ST29-infected cell results. However, in spite of the presence of IL-10, supernatants from ST28-infected DC induced IFN-γ production by T cells similarly to those from H37Rv-infected DC culture. On the other hand, IL-10 impaired CXCL10 production in sigE mutant-infected DC and, indeed, its neutralization restored CXCL10 secretion. In line with these results, supernatants from ST28-infected cells showed a decreased capability to recruit CXCR3+ CD4+ T cells compared to those obtained from H37Rv-infected DC culture. Thus, our findings suggest that the sigE mutant-induced secretion of IL-10 inhibits CXCL10 expression and, in turn, the recruitment of activated-effector cells involved in the formation of granulomas.

scholarly journals Antibodies against Listerial Protein 60 Act as an Opsonin for Phagocytosis of Listeria monocytogenes by Human Dendritic Cells

2001 ◽  
Vol 69 (5) ◽  
pp. 3100-3109 ◽  
Author(s):  
Annette Kolb-Mäurer ◽  
Sabine Pilgrim ◽  
Eckhart Kämpgen ◽  
Alexander D. McLellan ◽  
Eva-Bettina Bröcker ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Listeria Monocytogenes ◽  
Human Plasma ◽  
Systemic Infection ◽  
Human Monocyte ◽  
Serovar Typhimurium ◽  
Efficient Uptake ◽  
A Minor ◽  
Human Dendritic Cells ◽  
Systemic Infections

ABSTRACT Human-monocyte-derived dendritic cells (MoDC) are very efficient in the uptake of Listeria monocytogenes, a gram-positive bacterium which is an important pathogen in humans and animals causing systemic infections with symptoms such as septicemia and meningitis. In this work, we analyzed the influence of blood plasma on the internalization of L. monocytogenes into human MoDC and compared the uptake of L. monocytogenes with that ofSalmonella enterica serovar Typhimurium and Yersinia enterocolitica. While human plasma did not significantly influence the uptake of serovar Typhimurium and Y. enterocolitica by human MoDC, the efficiency of the uptake ofL. monocytogenes by these phagocytes was strongly enhanced by human plasma. In plasma-free medium the internalization of L. monocytogenes was very low, whereas the addition of pooled human immunoglobulins resulted in the internalization of these bacteria to a degree comparable to the highly efficient uptake observed with human plasma. All human plasma tested contained antibodies against the 60-kDa extracellular protein of L. monocytogenes (p60), and anti-p60 antibodies were also found in the commercially available pooled immunoglobulins. Strikingly, in contrast to L. monocytogenes wild type, an iap deletion mutant (totally deficient in p60) showed only a minor difference in the uptake by human MoDC in the presence or the absence of human plasma. These results support the assumption that antibodies against the listerial p60 protein may play an important role in Fc-receptor-mediated uptake of L. monocytogenes by human MoDC via opsonization of the bacteria. This process may have a major impact in preventing systemic infection in L. monocytogenes in immunocompetent humans.

scholarly journals Contrasting Effects of Human, Canine, and Hybrid Adenovirus Vectors on the Phenotypical and Functional Maturation of Human Dendritic Cells: Implications for Clinical Efficacy

2007 ◽  
Vol 81 (7) ◽  
pp. 3272-3284 ◽  
Author(s):  
Matthieu Perreau ◽  
Franck Mennechet ◽  
Nicolas Serratrice ◽  
Joel N. Glasgow ◽  
David T. Curiel ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Viral Vectors ◽  
Morphological Changes ◽  
Human Adenovirus ◽  
Human Monocyte ◽  
Necrosis Factor Alpha ◽  
Antigen Uptake ◽  
Functional Maturation ◽  
Human Dendritic Cells

ABSTRACT Antipathogen immune responses create a balance between immunity, tolerance, and immune evasion. However, during gene therapy most viral vectors are delivered in substantial doses and are incapable of expressing gene products that reduce the host's ability to detect transduced cells. Gene transfer efficacy is also modified by the in vivo transduction of dendritic cells (DC), which notably increases the immunogenicity of virions and vector-encoded genes. In this study, we evaluated parameters that are relevant to the use of canine adenovirus serotype 2 (CAV-2) vectors in the clinical setting by assaying their effect on human monocyte-derived DC (hMoDC). We compared CAV-2 to human adenovirus (HAd) vectors containing the wild-type virion, functional deletions in the penton base RGD motif, and the CAV-2 fiber knob. In contrast to the HAd type 5 (HAd5)-based vectors, CAV-2 poorly transduced hMoDC, provoked minimal upregulation of major histocompatibility complex class I/II and costimulatory molecules (CD40, CD80, and CD86), and induced negligible morphological changes indicative of DC maturation. Functional maturation assay results (e.g., reduced antigen uptake; tumor necrosis factor alpha, interleukin-1β [IL-1β], gamma interferon [IFN-γ], IL-10, IL-12, and IFN-α/β secretion; and stimulation of heterologous T-cell proliferation) were also significantly lower for CAV-2. Our data suggested that this was due, in part, to the use of an alternative receptor and a block in vesicular escape. Additionally, HAd5 vector-induced hMoDC maturation was independent of the aforementioned cytokines. Paradoxically, an HAd5/CAV-2 hybrid vector induced the greatest phenotypical and functional maturation of hMoDC. Our data suggest that CAV-2 and the HAd5/CAV-2 vector may be the antithesis of Adenoviridae immunogenicity and that each may have specific clinical advantages.

Proteasome Inhibitors Affect the Function of Human Dendritic Cells and Induce Caspase-Mediated Apoptosis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2229-2229
Author(s):  
Karin von Schwarzenberg ◽  
Alessio Nencioni ◽  
Anita Bringmann ◽  
Lothar Kanz ◽  
Franco Patrone ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Proteasome Inhibitors ◽  
Human Monocyte ◽  
Proteasome Inhibition ◽  
Parp Cleavage ◽  
Induced Apoptosis ◽  
And Function ◽  
Human Dendritic Cells

Abstract Proteasome inhibitors (PI) show antitumor activity against a broad spectrum of human malignancies both in vitro and in vivo. Yet, the consequences of exposure to these compounds on the immune system still have to be clearly determined. In the present study, we have investigated the effect of the proteasome inhibitors on human monocyte-derived dendritic cells (DCs). Exposure to PI results in a reduced activation induced DC maturation and cytokine production, inhibition of their migratory capacity and impaired ability to stimulate T-cell responses. These functional and phenotypic alterations were paralleled by a decreased phosphorylation of the MAP kinase member ERK1/2 while not affecting p38. Furthermore, incubation of DC with bortezomib inhibited the expression of nuclear localized transcription factors that were shown to be important for DC differentiation and function like IRF3, Rel-b and c-rel. Addition of PI to culture medium induced apoptosis of differentiated DCs and strongly reduced the yield of viable DCs when given to monocytes before differentiation to DCs was induced. DC apoptosis was accompanied by caspase activation as detected by caspase-3 and PARP cleavage. Cytochrome c cytosolic relocalization was detectable following exposure to bortezomib and was not prevented by caspase inhibition. This points to the mitochondrial damage as to an upstream event in DC apoptosis via proteasome inhibition. While not affecting Bcl-2 levels, bortezomib was found to promote Bax upregulation in DCs, thus providing a possible explanation for mitochondria dysfunction in response to this compound. In conclusion, this study shows that besides the inhibition of Nf-kB bortezomib is affecting several other pivotal signal transduction pathways in human cells and suggests that inhibition of DC function and induction of apoptosis in DCs may represent a mechanism by which bortezomib can affect the immune responses in patients treated with this compound.

scholarly journals Effects of Staphylococcus aureus Bacteriophage K on Expression of Cytokines and Activation Markers by Human Dendritic Cells In Vitro

Viruses ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 617 ◽  
Author(s):  
Helen Freyberger ◽  
Yunxiu He ◽  
Amanda Roth ◽  
Mikeljon Nikolich ◽  
Andrey Filippov
Keyword(s):  
Staphylococcus Aureus ◽  
Dendritic Cells ◽  
Inflammatory Response ◽  
Adaptive Immune Response ◽  
Human Monocyte ◽  
Activation Markers ◽  
Mhc I ◽  
Adaptive Immune ◽  
Human Dendritic Cells

A potential concern with bacteriophage (phage) therapeutics is a host-versus-phage response in which the immune system may neutralize or destroy phage particles and thus impair therapeutic efficacy, or a strong inflammatory response to repeated phage exposure might endanger the patient. Current literature is discrepant with regard to the nature and magnitude of innate and adaptive immune response to phages. The purpose of this work was to study the potential effects of Staphylococcus aureus phage K on the activation of human monocyte-derived dendritic cells. Since phage K acquired from ATCC was isolated around 90 years ago, we first tested its activity against a panel of 36 diverse S. aureus clinical isolates from military patients and found that it was lytic against 30/36 (83%) of strains. Human monocyte-derived dendritic cells were used to test for an in vitro phage-specific inflammatory response. Repeated experiments demonstrated that phage K had little impact on the expression of pro- and anti-inflammatory cytokines, or on MHC-I/II and CD80/CD86 protein expression. Given that dendritic cells are potent antigen-presenting cells and messengers between the innate and the adaptive immune systems, our results suggest that phage K does not independently affect cellular immunity or has a very limited impact on it.

scholarly journals CRISPR-based functional genomics in human dendritic cells

2020 ◽  
Author(s):  
Marco Jost ◽  
Amy N. Jacobson ◽  
Jeffrey A. Hussmann ◽  
Giana Cirolia ◽  
Michael A. Fischbach ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Genome Editing ◽  
Individual Variation ◽  
Human Microbiome ◽  
Human Monocyte ◽  
Genetic Screens ◽  
Mucosal Surfaces ◽  
Immune Phenotypes ◽  
Human Dendritic Cells

AbstractDendritic cells (DCs) regulate processes ranging from antitumor and antiviral immunity to host-microbe communication at mucosal surfaces. It remains difficult, however, to genetically manipulate human DCs, limiting our ability to probe how DCs elicit specific immune responses. Here, we develop a CRISPR/Cas9 genome editing method for human monocyte-derived DCs (moDCs) that mediates knockouts with a median efficiency of >93% across >300 genes. Using this method, we perform genetic screens in moDCs, identifying mechanisms by which DCs tune responses to lipopolysaccharides from the human microbiome. In addition, we reveal donor-specific responses to lipopolysaccharides, underscoring the importance of assessing immune phenotypes in donor-derived cells, and identify genes that control this specificity, highlighting the potential of our method to pinpoint determinants of inter-individual variation in immune responses. Our work sets the stage for a systematic dissection of the immune signaling at the host-microbiome interface and for targeted engineering of DCs for neoantigen vaccination.

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