Dendritic Cell, Toll-Like Receptor, and The Immune System (original) (raw)
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Journal of Experimental Medicine, 2001
Toll-like receptors (TLRs) are ancient microbial pattern recognition receptors highly conserved from Drosophila to humans. To investigate if subsets of human dendritic cell precursors (pre-DC), including monocytes (pre-DC1), plasmacytoid DC precursors (pre-DC2), and CD11c+ immature DCs (imDCs) are developed to recognize different microbes or microbial antigens, we studied their TLR expression and responses to microbial antigens. We demonstrate that whereas monocytes preferentially express TLR 1, 2, 4, 5, and 8, plasmacytoid pre-DC strongly express TLR 7 and 9. In accordance with these TLR expression profiles, monocytes respond to the known microbial ligands for TLR2 (peptidoglycan [PGN], lipoteichoic acid) and TLR4 (lipopolysaccharide), by producing tumor necrosis factor (TNF)-α and interleukin (IL)-6. In contrast, plasmacytoid pre-DCs only respond to the microbial TLR9-ligand, CpG-ODNs (oligodeoxynucleotides [ODNs] containing unmethylated CpG motifs), by producing IFN-α. CD11c+ imD...
Toll-like receptor ligand activation of murine bone marrow-derived dendritic cells
Immunology, 2009
Dendritic cells (DCs) are required for the initiation of primary immune responses. The pattern of Toll-like receptor (TLR) expression on various subsets of these cells has been shown to differ, suggestive of distinct roles in influencing immune responses. We have examined here the responses of immature DCs derived from murine bone marrow (BMDCs) to a range of TLR ligands. BMDCs cultured for 6 days in the presence of granulocyte-macrophage colony-stimulating factor were stimulated for 24 hr with ligands to TLR1-2 [Pam 3 Cys-Ser-(Lys) 4 (PAM)], TLR2-6 (macrophageactivating lipopeptide-2 (MALP-2); zymosan or peptidoglycan (PG)], TLR3 (polyinosinic-polycytidylic acid), TLR4 [lipopolysaccharide R515 (LPS)], TLR5 (flagellin), TLR7 (polyuridylic acid) and TLR9 [CpG ODN2395 (CpG)]. DC activation was monitored using membrane marker expression and analysis of culture supernatants for cytokine/chemokine release. Ligands to TLR3 and TLR7 failed to activate BMDCs. All other TLR ligands caused elevated expression of membrane markers. PAM, MALP-2 and LPS induced high-level expression of proinflammatory cytokines and chemokines. Treatment with CpG was associated with a preferential type 1 cytokine and chemokine profile. Zymosan and PG were proinflammatory but also skewed towards a type 2 pattern of cytokines and chemokines. In contrast, flagellin did not cause marked secretion by BMDCs of cytokines or chemokines. These data for BMDCs are largely consistent with the reported TLR repertoire of freshly isolated murine Langerhans cells. In addition, murine BMDCs show selective responses to TLR ligands with respect to general activation, with differentiated cytokine patterns suggestive of potential priming for divergent immune responses.
Regulation of Toll-Like Receptors in Human Monocytes and Dendritic Cells
The Journal of Immunology, 2001
A number of pathogens induce immature dendritic cells (iDC) to migrate to lymphoid organs where, as mature DC (mDC), they serve as efficient APC. We hypothesized that pathogen recognition by iDC is mediated by Toll-like receptors (TLRs), and asked which TLRs are expressed during the progression of monocytes to mDC. We first measured mRNA levels for TLRs 1-5 and MD2 (a protein required for TLR4 function) by Northern analysis. For most TLRs, message expression decreased severalfold as monocytes differentiated into iDC, but opposing this trend, TLR3 and MD2 showed marked increases during iDC formation. When iDC were induced to mature with LPS or TNF-␣, expression of most TLRs transiently increased and then nearly disappeared. Stimulation of iDC, but not mDC, with LPS resulted in the activation of IL-1 receptor-associated kinase, an early component in the TLR signaling pathway, strongly suggesting that LPS signals through a TLR. Surface expression of TLRs 1 and 4, as measured by mAb binding, was very low, corresponding to a few thousand molecules per cell in monocytes, and a few hundred or less in iDC. We conclude that TLRs are expressed in iDC and are involved in responses to at least one pathogenderived substance, LPS. If TLR4 is solely responsible for LPS signaling in humans, as it is in mice, then its extremely low surface expression implies that it is a very efficient signal transducer in iDC.
Toll-like receptor mRNA expression patterns in human dendritic cells and monocytes
The innate immune system recognises a wide spectrum of pathogens without a need for prior exposure. The main cells responsible aremonocytes, macrophages, dendritic cells (DC) and neutrophils phagocytose microbial pathogens triggering a cytokine network resulting inthe development of inflammatory and specific immune responses. Findings in the Toll-like receptor (TLR) family, initially discovered inDrosophila, further elucidated these processes. Toll-like receptors induce activation of an innate immune response and at present ten TLRshave been identified, named TLRs 1–10. In addition to the ignition of the innate immune response, evidence implicates the TLR family ina spectrum of systemic disorders following bacterial infections including sepsis and multiple organ failure, and can be detrimental, leadingto tissue injury. In this project, our main goal was to investigate the effects of a TLR4 ligand, lipolysaccharide (LPS) in human DC andmonocytes. Our hypothesis is that different professional APCs, express different mRNA TLR transcripts. Our findings indicate that TLRexpression patterns change in relation to the pathogen involved and in the case of DC, and the maturation stage the latter are upon challenging.Our results and interpretation showed significant alteration of transcript expression patterns upon LPS challenge in all cell subsets, with DCsubsets expressing different TLR mRNA patterns as they go through different maturation stages.
Regulation of antigen uptake, migration, and lifespan of dendritic cell by Toll-like receptors
Journal of Molecular Medicine, 2010
Dendritic cells (DCs) sense the presence of pathogens through germline-encoded pattern recognition receptors (PRRs), which recognize molecular patterns expressed by various microorganisms and endogenous stimuli. Toll-like receptors (TLRs) are the best characterized PRRs. TLR activation has a profound effect on a number of DC activities, including endocytosis, cytoskeleton rearrangement, migration, antigen processing and presentation, survival, and death. The goal of TLRinduced DC reprogramming is to promote the appropriate activation and differentiation of lymphocytes bearing clonally distributed antigen-specific receptors. In this review, we will focus on the functional consequences of TLR engagement for conventional DCs.
Immunity, 2008
Toll-like receptors (TLRs) play prominent roles in initiating adaptive immune responses to infection, but their roles in particular cell types in vivo are not established. Here we report the generation of mice selectively lacking the crucial TLR-signaling adaptor MyD88 in dendritic cells (DCs). In these mice, the early production of inflammatory cytokines, especially IL-12, was substantially reduced following TLR stimulation. Whereas, the innate interferon γ response of natural killer cells and natural killer T cells, and T H 1 polarization of antigen-specific CD4 T cells were severely compromised after treatment with a soluble TLR9 ligand, they were largely intact following administration of an aggregated TLR9 ligand. These results demonstrate that the physical form of a TLR ligand affects which cells can respond to it and that DCs and other innate immune cells can respond via TLRs and collaborate in promoting T H 1 adaptive immune responses to an aggregated stimulus.
The activation of the adaptive immune system is generally dependent on antigen presenting cells i.e. dendritic cells and macrophages. One of members which are already present on dendritic cells i.e. Toll-like receptor is key regulators of both innate and adaptive immune responses. Accordingly, recent evidence from human studies and experimental animal models studies which implicates that toll like receptors played an important role in vaccine development. However, fundamental questions remain unanswered concerning the actual role of toll like receptors in dendritic cell. In this review, we discuss the proposed roles of toll like receptors in dendritic cells and correlates with vaccine development.
Proximal effects of Toll-like receptor activation in dendritic cells
Current Opinion in Immunology, 2007
Toll-like receptor (TLR) signals induce dendritic cell (DC) differentiation and influence the immunological outcome of their interactions with T cells. Recent in vitro studies demonstrate that TLR signals also trigger striking reorganisation of the DC vacuolar compartments, the cytoskeleton and the machinery of protein translation and turnover. Moreover, TLR ligation within endosomes and phagosomes appears to establish organelle autonomous signals. These changes, which mostly occur within minutes to a few hours after TLR engagement, are adaptations relevant to the antigen capture, processing and migratory phases of the DC life history.
American journal of clinical and experimental immunology, 2013
Dendritic cells (DCs) represent a functionally diverse and flexible population of rare cells with the unique capability of binding, internalizing and detecting various microorganisms and their components. However, the response of DCs to innocuous or pathogenic microbes is highly dependent on the type of microbe-associated molecular patterns (MAMPs) recognized by pattern recognition receptors (PRRs) that interact with phylogenetically conserved and functionally indispensable microbial targets that involve both self and foreign structures such as lipids, carbohydrates, proteins, and nucleic acids. Recently, special attention has been drawn to nucleic acid receptors that are able to evoke robust innate immune responses mediated by type I interferons and inflammatory cytokine production against intracellular pathogens. Both conventional and plasmacytoid dendritic cells (cDCs and pDCs) express specific nucleic acid recognizing receptors, such as members of the membrane Toll-like receptor...