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Author: Brendan Cordeiro
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
"Dendritic cells (DCs) are antigen-presenting cells and are central regulators of the adaptive immune system. DCs are found in a steady state, poised to respond to activating stimuli. Once stimulated, they rapidly undergo dynamic changes in gene expression to adopt an activated phenotype capable of promoting the differentiation of T cell lineages against the particular threat. The exact mechanisms regulating the transition from steady state to activation of DCs are not well understood. In this work, we explored two novel mechanisms of DC regulation. The first mechanism examined involves microRNA-9 (miR-9). MicroRNAs are emerging as important regulators of immune function due to their fast action and ability to regulate programs of gene expression. We found that miR-9 was upregulated in both bone marrow-derived DCs (BMDCs) and conventional DC1s but not in conventional DC2s following stimulation. miR-9 expression in BMDCs and conventional DC1s promotes enhanced DC activation and function, including the ability to stimulate T cell activation and control tumor growth. We then found that miR-9 reduced the expression of a group of negative regulators, including the transcriptional repressor Polycomb group factor 6. The second mechanism explored involves the Cystic fibrosis transmembrane conductance regulator (CFTR). Cystic fibrosis is an incurable genetic disease caused by loss of function of the CFTR gene. CFTR loss leads to the creation of an environment suitable for colonization by various pathogenic bacteria in both the lungs and the intestines. Cystic fibrosis patients display an increase in inflammatory signalling that is cell intrinsic and not due to bacterial colonization, while also showing an increased risk for multiple autoimmune and inflammatory conditions. DCs express CFTR and mice with CFTR knocked out specifically in CD11c expressing cells exhibited increased activation of intestinal DCs which promoted the activation of Th17+ CD4+ T cells. This correlated with a defect in early immune responses towards the intestinal pathogen C. rodentium. Finally, we found that loss of CFTR inhibits anti-inflammatory PI3K-Akt signaling in DCs, which may provide a starting point to understand the mechanism linking CFTR and DC regulation. In summary, this work establishes the novel roles of miR-9 and CFTR in the molecular regulation of DC activation and function"--
Author: Brendan Cordeiro
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
"Dendritic cells (DCs) are antigen-presenting cells and are central regulators of the adaptive immune system. DCs are found in a steady state, poised to respond to activating stimuli. Once stimulated, they rapidly undergo dynamic changes in gene expression to adopt an activated phenotype capable of promoting the differentiation of T cell lineages against the particular threat. The exact mechanisms regulating the transition from steady state to activation of DCs are not well understood. In this work, we explored two novel mechanisms of DC regulation. The first mechanism examined involves microRNA-9 (miR-9). MicroRNAs are emerging as important regulators of immune function due to their fast action and ability to regulate programs of gene expression. We found that miR-9 was upregulated in both bone marrow-derived DCs (BMDCs) and conventional DC1s but not in conventional DC2s following stimulation. miR-9 expression in BMDCs and conventional DC1s promotes enhanced DC activation and function, including the ability to stimulate T cell activation and control tumor growth. We then found that miR-9 reduced the expression of a group of negative regulators, including the transcriptional repressor Polycomb group factor 6. The second mechanism explored involves the Cystic fibrosis transmembrane conductance regulator (CFTR). Cystic fibrosis is an incurable genetic disease caused by loss of function of the CFTR gene. CFTR loss leads to the creation of an environment suitable for colonization by various pathogenic bacteria in both the lungs and the intestines. Cystic fibrosis patients display an increase in inflammatory signalling that is cell intrinsic and not due to bacterial colonization, while also showing an increased risk for multiple autoimmune and inflammatory conditions. DCs express CFTR and mice with CFTR knocked out specifically in CD11c expressing cells exhibited increased activation of intestinal DCs which promoted the activation of Th17+ CD4+ T cells. This correlated with a defect in early immune responses towards the intestinal pathogen C. rodentium. Finally, we found that loss of CFTR inhibits anti-inflammatory PI3K-Akt signaling in DCs, which may provide a starting point to understand the mechanism linking CFTR and DC regulation. In summary, this work establishes the novel roles of miR-9 and CFTR in the molecular regulation of DC activation and function"--
Author: Fang Zhou
Publisher: Frontiers Media SA
ISBN: 2832547702
Category : Medical
Languages : en
Pages : 213
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Book Description
Dendritic cells (DCs) play a critical role in immune system, as they are necessary both for innate and adaptive immunity. According to their function, dendritic cells can be classified in immune tolerogenic or inflammatory DCs. DCs have been shown to regulate T cell-mediated immune responses and lead to immune tolerance and autoimmunity. For example, immune-tolerogenic DCs facilitate the development of regulatory T cells and inhibit T helper 17-mediated autoimmunity in mice with experimental autoimmune encephalomyelitis. Moreover, inflammatory DCs activate CD8+ and CD4+ T cells and elicit T cell-mediated inflammatory immune responses in vivo. However, the molecular and cellular mechanisms underlying DC-mediated immune tolerance and autoimmunity are still obscure.
Author: Penelope Anne Morel
Publisher: Frontiers Media SA
ISBN: 2889198685
Category : Dendritic cells
Languages : en
Pages : 123
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Book Description
Dendritic cells (DC) are among the first cells to encounter pathogens and damage in peripheral tissues and, upon activation, DC migrate to lymph nodes where they activate and educate T cells to initiate and shape the immune response. DC present pathogen-derived antigen to T cells and drive T cell differentiation into particular effector cells through the expression and secretion of co-stimulatory molecules and cytokines respectively. The study of DC biology has included the identification of multiple DC subsets in tissues and lymphoid organs, the differentiation and plasticity of DC subsets, the functional consequences of DC interaction with pathogen, control of DC migratory properties and the impact of DC on T cell activation and differentiation. In recent years sophisticated systems biology approaches have been developed to deepen our understanding of DC function. These studies have identified differences between DC subsets located in various tissues and critical factors that drive the outcome of the interaction between DC and T cells. DC are currently being used in in various clinical therapeutic settings, including as vaccines for cancer and autoimmune disease. A clear understanding of DC factors that contribute to specific immune responses is vital to the success of DC based therapies. This research topic will give a comprehensive overview of current issues in DC biology and provides an update on the clinical uses of DC in the therapy of autoimmunity and cancer.
Author: Sudhir Gupta
Publisher: Springer Science & Business Media
ISBN: 0387241809
Category : Medical
Languages : en
Pages : 160
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Book Description
This volume is edited by Dr. Sudhir Gupta, internationally recognized expert in Immunology, Professor of Medicine, Pathology, Microbiology and Molecular Genetics. Topics include toll receptors, dendritic cells, NK cells, and complement receptors.
Author: Francesca Granucci
Publisher: Frontiers E-books
ISBN: 288919230X
Category :
Languages : en
Pages : 153
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Book Description
One of the most interesting issues in immunology is how the innate and adaptive branches of the immune system cooperate in vertebrate organisms to respond and destroy invading microorganisms without destroying self-tissues. More than 20 years ago, Charles Janeway proposed the innate immune recognition theory [1]. He hypothesized the existence of innate receptors (Pattern recognition receptors, PRRs) that, by recognizing molecular structures associated to pathogens (PAMPs) and being expressed by antigen presenting cells (APCs) and epithelial cells, could alert the immune system to the presence of a pathogen, making it possible to mount an immediate inflammatory response. Moreover, by transducing the alert signal in professional APCs and inducing the expression of costimulatory molecules, these receptors could control the activation of lymphocytes bearing clonal antigen-specific receptors, thereby promoting appropriate adaptive immune responses. Since adaptive immunity can be activated also following sterile inflammatory conditions, it was subsequently proposed by Polly Matzinger that the innate immune system could be also activated by endogenous danger signals, generically called danger associated molecular patterns (DAMPs)[2]. The first prediction has been amply confirmed by the discovery of Toll-like receptors [3; 4; 5] and cytoplasmic PRRs such as RIG-like receptors [6]. Other PRR families such as the NOD-like receptors and C-type lectins exert immunogenic or tolerogenic signals [7; 8; 9] and may recognize not strictly pathogens but also endogenous danger signals that may lead to inflammasome activation [10; 11] . Dendritic cells (DCs) have been identified as the cells of the innate immune system that, by sensing PAMPs or DAMPs transduce signals to the nucleus. This leads to a transcriptional reprogramming of DCs with the consequent expression of three signals, namely signal 1 (MHC+peptide), signal 2 (surface costimulatory molecules) and signal 3 (cytokines) necessary for the priming of antigen-specific naïve T cell responses (signal 1 and 2) and T cell polarization (signal 3). The reason why DCs are superior with respect to other professional APCs in naïve T cell activation has not been unequivocally defined but in vivo may mainly result from their migration capacity to secondary lymphoid organs. It has not been established whether DCs can provide a special “signal 2” or simply very high levels, compared with other APCs, of commonly expressed signals 1 and 2, so that a naïve T cell could reach the threshold of activation. A second aspect of DC biology needs also to be taken into account. Concerning the question of how self-tissues are not destroyed following the initiation of adaptive immune responses, different mechanisms of central and peripheral auto-reactive T cell tolerization have been proposed [12]. In particular, it has been defined that high affinity T cells are deleted in the thymus, while low affinity auto-reactive T cells or T cells specific for tissue-sequestered antigens that do not have access to the thymus are controlled in the periphery. In a simplified vision of how peripheral T cell tolerance could be induced and maintained, it was thought that, in resting conditions, immature DCs, expressing low levels of signal 1 and low or no levels of signal 2, were able to induce T cell unresponsiveness. Nevertheless, it is now clear that a fundamental contribution to the peripheral tolerance is due to the conversion of naïve T cells into peripheral regulatory T cells (pTreg cells) and it is also clear that DCs need to receive a specific conditioning to become able to induce pTreg cell differentiation. Even more intriguing is that also DCs activated through PRRs, with particular Toll like receptor (TLR) agonists, are capable of generating pTreg cell conversion if these agonists induce the production of the appropriate cytokines.
Author: Hannah Guak
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
"Dendritic cells (DCs) are innate immune cells that are specialized to sense their microenvironment, integrate the signals they receive, and convey this message to initiate adaptive immunity, thereby shaping the nature of the immune response. Cellular metabolism has been established to be a critical molecular mechanism regulating the function and activation of immune cells, including those of DCs. In this thesis, I highlight our findings on how different aspects of metabolism, including glycolysis, oxidative metabolism, and changes in whole-body metabolism, influence DC function and activation. Strong Toll-like receptor stimulation has previously been shown to rapidly induce glycolysis to fuel fatty acid synthesis and consequent membrane expansion. We show that weak activation of DCs also increases their early glycolytic activity, suggesting that enhanced glycolysis is a hallmark of DC activation regardless of the strength of stimulation. Only the highly pro-inflammatory DCs, however, undergo long-term glycolytic reprogramming that is associated with active HIF-1, a transcription factor that promotes glycolysis. We then assessed the role of glycolysis in a fundamental process of DCs—cellular migration. We found that glycolysis is required for spontaneous DC motility as well as chemokine-induced DC migration by promoting oligomerization of the chemokine receptor CCR7. In addition, we show that inhibition of glycolysis impairs DC migration in a house dust mite-induced allergic asthma model in vivo. While glycolytic regulation of DC function and activation has been relatively well-studied, there is less known about the role of mitochondrial metabolism. Therefore, we next investigated the role of a major regulator of mitochondrial metabolism, the transcriptional co-activator PGC-1, in DCs. Bioenergetic profiles of PGC-1-deficient DCs reveal an impairment of oxidative metabolism and concurrent increase in glycolytic activity. Lipopolysaccharide-activated DCs, which downregulate PGC-1 gene expression and lose oxidative capacity over time, do not rely on PGC-1 for their bioenergetics. In contrast, interferon-beta-treated DCs maintain PGC-1 gene expression and mitochondrial metabolism, and rely on PGC-1 for optimal bioenergetic capacity. PGC-1 deficiency also affects the immune function of DCs by promoting T cell expansion and type 2 T helper cell differentiation. We next examined conventional DC (cDC) subsets in vivo, comparing and characterizing their mitochondrial and lipid content across different tissues. We found that these metabolic features differ between cDC subsets across tissues, establishing that the specific tissue microenvironment they reside in influences these phenotypes. When challenged with a metabolic perturbation such as high-fat diet feeding, levels of intracellular lipid increase considerably, while mitochondrial mass is greatly diminished. Collectively, our findings both expand our understanding and underscore the importance of metabolic programming in regulating DC biology"--
Author: Michael T. Lotze
Publisher:
ISBN:
Category : Medical
Languages : en
Pages : 808
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Book Description
Dendritic Cells is the first definitive book on this subject, and brings together the most current information in the field for scientists and clinicians. It outlines research studies, the first reports of therapeutic applications of dendritic cells, and the enormous potential of these unique cells. Contributors are from the key research groups around the world who are working on the immunobiology of dendritic cells and in applied areas, striving to develop their therapeutic potential.
Author: Michael R Shurin
Publisher: Springer Science & Business Media
ISBN: 0387886117
Category : Medical
Languages : en
Pages : 394
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Book Description
It covers all aspects of DC generation, function, survival and antitumor activity in the tumor environment both in vivo and in experimental in vitro systems. The goal in focusing on a spectrum of issues related to DC in cancer is to provide an extensive and expansive review rather than a collection of independent analyses from different authors. Specific topics to be covered include analysis of DC behavior in the tumor microenvironment, including endogenous and exogenous DC, multiple DC populations, molecular pathways responsible for DC dysfunction, tumor-derived factors altering DC polarization and activation, mechanisms of DC alterations, and the role of DC in tumor escape from immune recognition and elimination. Furthermore, additional chapters provide extensive analysis of the consequences of cancer therapy on the DC system and how aging impacts DC function in the tumor microenvironment. Finally, chapters are included examining strengths and pitfalls of current methodologies for generating DC from cancer patients for therapeutic purposes and on the role of tumor-mediated modulation of the DC system in cancer immunotherapy.
Author: Sudhir Gupta
Publisher: Springer Science & Business Media
ISBN: 1461553555
Category : Medical
Languages : en
Pages : 222
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Book Description
Proceedings of the Seventh International Conference held in New Port Beach, California, February 6-8, 1998
Author: Gerold Schuler
Publisher: CRC Press
ISBN: 9780849356469
Category : Medical
Languages : en
Pages : 336
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Book Description
Epidermal Langerhans Cells focuses on epidermal Langerhans cells (LCs) and the important role they play in the induction of contact hypersensitivity and graft rejection. This in-depth work discusses how these antigen-presenting cells are modulated by various physicochemical agents (such as UV light) and how they can be infected by the AIDS virus. It also reveals that cytokines mediate their development into potent T cell-stimulatory dendritic cells. This comprehensive review covers important experimental details and methods, and fascinating information on LCs. It also provides an overview of the immune system as it relates to the skin in health and disease. This up-to-date publication is an indispensable resource for all investigative and clinical dermatologists, as well as immunologists interested in antigen-presenting cells.
