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Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8þ T cell tolerance. J Exp Med 196:1627–1638
, 2002
"... To identify endocytic receptors that allow dendritic cells (DCs) to capture and present antigens on major histocompatibility complex (MHC) class I products in vivo, we evaluated DEC-205, which is abundant on DCs in lymphoid tissues. Ovalbumin (OVA) protein, when chemically coupled to monoclonal �DEC ..."
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To identify endocytic receptors that allow dendritic cells (DCs) to capture and present antigens on major histocompatibility complex (MHC) class I products in vivo, we evaluated DEC-205, which is abundant on DCs in lymphoid tissues. Ovalbumin (OVA) protein, when chemically coupled to monoclonal �DEC-205 antibody, was presented by CD11c � lymph node DCs, but not by CD11c � cells, to OVA-specific, CD4 � and CD8 � T cells. Receptor-mediated presentation was at least 400 times more efficient than unconjugated OVA and, for MHC class I, the DCs had to express transporter of antigenic peptides (TAP) transporters. When �DEC-205:OVA was injected subcutaneously, OVA protein was identified over a 4–48 h period in DCs, primarily in the lymph nodes draining the injection site. In vivo, the OVA protein was selectively presented by DCs to TCR transgenic CD8 � cells, again at least 400 times more effectively than soluble OVA and in a TAP-dependent fashion. Targeting of �DEC-205:OVA to DCs in the steady state initially induced 4–7 cycles of T cell division, but the T cells were then deleted and the mice became specifically unresponsive to rechallenge with OVA in complete Freund’s adjuvant. In contrast, simultaneous delivery of a DC maturation stimulus via CD40, together
Bone marrow stromal cell antigen 2 is a specific marker of type I IFN-producing cells in the naive mouse, but a promiscuous cell surface antigen following IFN stimulation
- J. Immunol
, 2006
"... Type I IFN-producing cells (IPC) are sentinels of viral infections. Identification and functional characterization of these cells have been difficult because of their small numbers in blood and tissues and their complex cell surface phenotype. To overcome this problem in mice, mAbs recognizing IPC-s ..."
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Cited by 70 (0 self)
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Type I IFN-producing cells (IPC) are sentinels of viral infections. Identification and functional characterization of these cells have been difficult because of their small numbers in blood and tissues and their complex cell surface phenotype. To overcome this problem in mice, mAbs recognizing IPC-specific cell surface molecules have been generated. In this study, we report the identi-fication of new Abs specific for mouse IPC, which recognize the bone marrow stromal cell Ag 2 (BST2). Interestingly, previously reported IPC-specific Abs 120G8 and plasmacytoid dendritic cell Ag-1 also recognize BST2. BST2 is predominantly specific for mouse IPC in naive mice, but is up-regulated on most cell types following stimulation with type I IFNs and IFN-. The activation-induced promiscuous expression of BST2 described in this study has important implications for the use of anti-BST2 Abs in identification and depletion of IPC. Finally, we show that BST2 resides within an intracellular compartment corresponding to the Golgi apparatus, and may be involved in trafficking secreted cytokines in IPC. The Journal of Immunology, 2006, 177: 3260– 3265. T ype I IFN-producing cells (IPC),3 also called plasmacy-toid dendritic cells (DC), are early responders to viralinfections (1, 2). IPC detect viruses through TLRs 7 and 9 (3) and produce large amounts of type I IFN, i.e., IFN- and IFN- and proinflammatory chemokines. Through secretion of type I IFN, IPC direct both the innate and adaptive immune re-sponse by promoting NK cell and CD8 T cell cytotoxicity, en-hancing DC maturation, presenting Ag to T cells and inducing their Th1 polarization, and inducing B cell differentiation into Ab-secreting plasma cells (1, 2). IPC develop in the bone marrow and then circulate through the blood, eventually migrating into lym-phoid and nonlymphoid organs (1, 2), with increased recruitment into sites of inflammation (4, 5). Although IPC have significant effects on other cells, their numbers in blood and tissues are very small. This along with their complex surface phenotype makes them extremely difficult to identify. Specifically, mouse IPC are
The CD8 � dendritic cell subset selectively endocytoses dying cells in culture and
, 2002
"... Dendritic cells (DCs) are able in tissue culture to phagocytose and present antigens derived from infected, malignant, and allogeneic cells. Here we show directly that DCs in situ take up these types of cells after fluorescent labeling with carboxyfluorescein succinimidyl ester (CFSE) and injection ..."
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Cited by 58 (7 self)
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Dendritic cells (DCs) are able in tissue culture to phagocytose and present antigens derived from infected, malignant, and allogeneic cells. Here we show directly that DCs in situ take up these types of cells after fluorescent labeling with carboxyfluorescein succinimidyl ester (CFSE) and injection into mice. The injected cells include syngeneic splenocytes and tumor cell lines, induced to undergo apoptosis ex vivo by exposure to osmotic shock, and allogeneic B cells killed by NK cells in situ. The CFSE-labeled cells in each case are actively endocytosed by DCs in vivo, but only the CD8 � subset. After uptake, all of the phagocytic CD8 � DCs can form major histocompatibility complex class II–peptide complexes, as detected with a monoclonal antibody specific for these complexes. The CD8 � DCs also selectively present cell-associated antigens to both CD4 � and CD8 � T cells. Similar events take place with cultured DCs; CD8 � DCs again selectively take up and present dying cells. In contrast, both CD8 � and CD8 � DCs phagocytose latex particles in culture, and both DC subsets present soluble ovalbumin captured in vivo. Therefore CD8 � DCs are specialized to capture dying cells, and this helps to explain their selective ability to cross present cellular antigens to both CD4 � and CD8 � T cells. Key words: dendritic cells • cross-presentation • apoptosis • dendritic cell subset • CD8 � dendritic cell
Mouse strain differences in plasmacytoid dendritic cell frequency and function revealed by a novel monoclonal antibody
- J. Immunol
, 2003
"... We report in this study the generation of a novel rat mAb that recognizes mouse plasmacytoid dendritic cells (pDC). This Ab, named 120G8, stains a small subset of CD11clow spleen cell with high specificity. This population produces high amounts of IFN- upon in vitro viral stimulation. Both ex vivo- ..."
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Cited by 46 (3 self)
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We report in this study the generation of a novel rat mAb that recognizes mouse plasmacytoid dendritic cells (pDC). This Ab, named 120G8, stains a small subset of CD11clow spleen cell with high specificity. This population produces high amounts of IFN- upon in vitro viral stimulation. Both ex vivo- and in vitro-derived 120G8 cells display a phenotype identical with that of the previously described mouse pDC (B220highLy6ChighGr1lowCD11bCD11clow). Mice treated with 120G8 mAb are depleted of B220highLy6ChighCD11clow cells and have a much-reduced ability to produce IFN- in response to in vivo CpG stimulation. The mAb 120G8 stains all and only B220highLy6ChighCD11clow pDC in all lymphoid organs. Immunohistochemical studies performed with this mAb indicate that pDC are located in the T cell area of spleen, lymph nodes, and Peyer’s patches. Although the Ag recognized by 120G8 is not yet known, we show that its expression is up-regulated by type I IFN on B cells and DC. Using this mAb in immunofluorescence studies demonstrates strain- and organ-specific differences in the frequency of pDC and other DC subsets. 129Sv mice have a much higher frequency of pDC, together with a lower frequency of conventional CD8CD11chigh DC, compared with C57BL/6 mice, both in spleen and blood. The higher ability of 129Sv mice to produce IFN- in vivo is related to a higher number of pDC, but also to a higher ability of pDC from 129Sv mice to produce IFN- in vitro in response to viral stimulation. The Journal of Immunology, 2003, 171: 6466–6477. D endritic cells (DC)2 are APCs that initiate T cell-depen-dent immune responses (1). In humans, plasmacytoidDC (pDC) are a DC subset characterized by their ultra-structural resemblance to Ig-secreting plasma cells, their unique
Controlling the Toll road to dendritic cell polarization
, 2004
"... Abstract: The activation of dendritic cells (DC) via Toll-like receptors (TLRs) plays a decisive role in shaping the outcome of primary immune re-sponses. Following TLR engagement by microbial products, DC migrate from peripheral tissues to lymphoid organs and up-regulate major histocom-patibility c ..."
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Cited by 35 (0 self)
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Abstract: The activation of dendritic cells (DC) via Toll-like receptors (TLRs) plays a decisive role in shaping the outcome of primary immune re-sponses. Following TLR engagement by microbial products, DC migrate from peripheral tissues to lymphoid organs and up-regulate major histocom-patibility complex and costimulatory molecules, acquiring the unique capacity to prime pathogen-specific, naı̈ve T cells. In addition, DC determine the character of the ensuing immune response by secreting cytokines that drive the development of T cells into T helper cell type 1 (Th1), Th2, or T regulatory effector cells. Three major factors in-fluence the pattern of cytokines released by DC and accordingly, the Th balance: the lineage to which DC belong; the maturation stimulus; and inflammatory mediators present at the site of infec-tion. A major focus of this review is the capacity of DC to integrate these factors and elicit distinct classes of immune responses. J. Leukoc. Biol. 75:
under review
"... Establish a collaborative production-procurement system with contract portfolio approach ..."
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Cited by 18 (1 self)
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Establish a collaborative production-procurement system with contract portfolio approach
The role of dendritic cell C-type lectin receptors in HIV pathogenesis
- J Leukoc
"... Abstract: Dendritic cells play a major role in HIV pathogenesis. Epithelial dendritic cells appear to be one of the first cells infected after sexual trans-mission and transfer of the virus to CD4 lympho-cytes, simultaneously activating these cells to pro-duce high levels of HIV replication. Such tr ..."
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Cited by 11 (0 self)
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Abstract: Dendritic cells play a major role in HIV pathogenesis. Epithelial dendritic cells appear to be one of the first cells infected after sexual trans-mission and transfer of the virus to CD4 lympho-cytes, simultaneously activating these cells to pro-duce high levels of HIV replication. Such transfer may occur locally in inflamed mucosa or after den-dritic cells have matured and migrated to local lymph nodes. Therefore, the mechanism of bind-ing, internalization, infection and transfer of HIV to CD4 lymphocytes is of great interest. Recently, the role of the C-type lectin DC-SIGN as a dendritic cell receptor for HIV has been intensively studied with in vitro monocyte-derived dendritic cells. However, it is clear that other C-type lectin recep-
Plasmacytoid dendritic cells accumulate and secrete interferon alpha in lymph nodes of HIV-1 patients
- PLoS ONE
"... Circulating plasmacytoid dendritic cells (pDC) decline during HIV-1 infection, but at the same time they express markedly higher levels of interferon alpha (IFNa), which is associated with HIV-1 disease progression. Here we show an accumulation of pDC in lymph nodes (LN) of treatment-naïve HIV-1 pat ..."
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Cited by 7 (0 self)
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Circulating plasmacytoid dendritic cells (pDC) decline during HIV-1 infection, but at the same time they express markedly higher levels of interferon alpha (IFNa), which is associated with HIV-1 disease progression. Here we show an accumulation of pDC in lymph nodes (LN) of treatment-naïve HIV-1 patients. This phenomenon was associated with elevated expression of the LN homing marker, CCR7, on pDC in peripheral blood of HIV-1 patients, which conferred increased migratory capacity in response to CCR7 ligands in ex vivo functional assays. LN-homed pDC of HIV-1 patients presented higher CD40 and lower BDCA2 levels, but unchanged CD83 and CD86 expression. In addition, these cells expressed markedly higher amounts of IFNa compared to uninfected individuals, and were undergoing faster rates of cell death. These results demonstrate for the first time that in asymptomatic, untreated HIV-1 patients circulating pDC up-regulate CCR7 expression, accumulate in lymph nodes, and express high amounts of IFNa before undergoing cell death. Since IFNa inhibits cell proliferation and modulates immune responses, chronically high levels of this cytokine in LN of HIV-1 patients may impair differentiation and immune
Association of SIGNR1 with TLR4-MD-2 enhances signal transduction by recognition of LPS in gram-negative bacteria. Int. Immunol
, 2005
"... SIGNR1, a member of a new family of mouse C-type lectins, is expressed at high levels in macrophages (M/) within the splenic marginal zone, lymph node medulla, and in some strains, in peritoneal cavity. We previously reported that SIGNR1 captures gram-negative bacteria, such as Escherichia coli and ..."
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Cited by 6 (0 self)
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SIGNR1, a member of a new family of mouse C-type lectins, is expressed at high levels in macrophages (M/) within the splenic marginal zone, lymph node medulla, and in some strains, in peritoneal cavity. We previously reported that SIGNR1 captures gram-negative bacteria, such as Escherichia coli and Salmonella typhimurium, as well as Candida albicans. We have now investigated the precise ligands and innate responses that involve SIGNR1. The interaction of SIGNR1 with FITC–dextran and E. coli was completely inhibited by LPS from E. coli and Salmonella minnesota. Using LPS from various types of rough mutants of Salmonella, we found that SIGNR1 primarily recognizes oligosaccharides in the non-reductive end of the LPS core region. In transfectants, expression of SIGNR1 enhanced the oligomerization of Toll-like receptor (TLR) 4 molecules as well as the degradation of IjB-a after stimulation with E. coli under low-serum conditions. The enhanced TLR4 oligomerization was inhibited by pre-treatment of the cells with anti-SIGNR1 mAb or with mannan. A physical association between SIGNR1 and the TLR4–MD-2 complex was also observed by immunoprecipitation. Finally, we found that transfection of SIGNR1 into the macrophage-like RAW264.7 cells resulted in significant augmentation of cytokine production. These results suggest that SIGNR1 associates with TLR4 to capture gram-negative bacteria and facilitate signal transduction to activate innate M / responses.
Plasmacytoid dendritic cells contribute to systemic but not local antiviral responses to HSV infections. PLoS Pathog (2013
"... Plasmacytoid dendritic cells (pDC) produce type I interferons (IFN-I) and proinflammatory cytokines in response to viruses; however, their contribution to antiviral immunity in vivo is unclear. In this study, we investigated the impact of pDC depletion on local and systemic antiviral responses to he ..."
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Plasmacytoid dendritic cells (pDC) produce type I interferons (IFN-I) and proinflammatory cytokines in response to viruses; however, their contribution to antiviral immunity in vivo is unclear. In this study, we investigated the impact of pDC depletion on local and systemic antiviral responses to herpes simplex virus (HSV) infections using CLEC4C-DTR transgenic mice. We found that pDC do not appear to influence viral burden or survival after vaginal HSV-2 infection, nor do they seem to contribute to virus-specific CD8 T cell responses following subcutaneous HSV-1 infection. In contrast, pDC were important for early IFN-I production, proinflammatory cytokine production, NK cell activation and CD8 T cell responses during systemic HSV-2 and HSV-1 infections. Our data also indicate that unlike pDC, TLR3-expressing cells are important for promoting antiviral responses to HSV-1 regardless of the route of virus administration.
