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Journal ArticleDOI

Dendritic cell control of tolerogenic responses.

01 May 2011-Immunological Reviews (NIH Public Access)-Vol. 241, Iss: 1, pp 206-227
TL;DR: It is suggested that the innate control of tolerogenic responses can be viewed as different hierarchies of organization, in which DCs, their innate receptors and signaling networks, and their interactions with other cells and local microenvironments represent different levels of the hierarchy.
Abstract: One of the most fundamental problems in immunology is the seemingly schizophrenic ability of the immune system to launch robust immunity against pathogens, while acquiring and maintaining a state of tolerance to the body's own tissues and the trillions of commensal microorganisms and food antigens that confront it every day. A fundamental role for the innate immune system, particularly dendritic cells (DCs), in orchestrating immunological tolerance has been appreciated, but emerging studies have highlighted the nature of the innate receptors and the signaling pathways that program DCs to a tolerogenic state. Furthermore, several studies have emphasized the major role played by cellular interactions and the microenvironment in programming tolerogenic DCs. Here, we review these studies and suggest that the innate control of tolerogenic responses can be viewed as different hierarchies of organization, in which DCs, their innate receptors and signaling networks, and their interactions with other cells and local microenvironments represent different levels of the hierarchy.

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Citations
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Journal ArticleDOI
TL;DR: A protocol for the validation and use of intravascular staining to define innate and adaptive immune cells in mice is outlined and applied to leukocyte analyses in many tissues and its use in the contexts of lymphocytic choriomeningitis virus and Mycobacterium tuberculosis infections or solid tumors is described.
Abstract: Characterization of the cellular participants in tissue immune responses is crucial to understanding infection, cancer, autoimmunity, allergy, graft rejection and other immunological processes. Previous reports indicate that leukocytes in lung vasculature fail to be completely removed by perfusion. Several studies suggest that intravascular staining may discriminate between tissue-localized and blood-borne cells in the mouse lung. Here we outline a protocol for the validation and use of intravascular staining to define innate and adaptive immune cells in mice. We demonstrate application of this protocol to leukocyte analyses in many tissues and we describe its use in the contexts of lymphocytic choriomeningitis virus and Mycobacterium tuberculosis infections or solid tumors. Intravascular staining and organ isolation usually takes 5-30 min per mouse, with additional time required for any subsequent leukocyte isolation, staining and analysis. In summary, this simple protocol should help enable interpretable analyses of tissue immune responses.

561 citations

Journal ArticleDOI
24 Feb 2012-Immunity
TL;DR: CD103(+)CD11b(+) LPDCs, in addition to promoting long-term tolerance to ingested antigens, also rapidly produce IL-23 in response to detection of flagellin in the lamina propria.

443 citations


Cites background from "Dendritic cell control of tolerogen..."

  • ...Signals from the intestinal tissue microenvironment, including epithelial cell-derived thymic stromal lyphopoietin (TSLP) and bile acid retinoids, condition CD103CD11b LPDCs to preferentially generate T regulatory cells once these DCs have trafficked to the mesenteric lymph nodes (Manicassamy and Pulendran, 2011)....

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  • ...…tissue microenvironment, including epithelial cell-derived thymic stromal lyphopoietin (TSLP) and bile acid retinoids, condition CD103+CD11b+ LPDCs to preferentially generate T regulatory cells once these DCs have trafficked to the mesenteric lymph nodes (Manicassamy and Pulendran, 2011)....

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Journal ArticleDOI
TL;DR: The use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists is described.
Abstract: Current treatments to control pathological or unwanted immune responses often use broadly immunosuppressive drugs. New approaches to induce antigen-specific immunological tolerance that control both cellular and humoral immune responses are desirable. Here we describe the use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists. Treatment with tolerogenic nanoparticles results in the inhibition of CD4+ and CD8+ T-cell activation, an increase in regulatory cells, durable B-cell tolerance resistant to multiple immunogenic challenges, and the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis, and antibody responses against coagulation factor VIII in hemophilia A mice, even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. Tolerogenic nanoparticle therapy represents a potential novel approach for the treatment of allergies, autoimmune diseases, and prevention of antidrug antibodies against biologic therapies.

342 citations

Journal ArticleDOI
TL;DR: NLRC4-dependent production of IL-1β by intestinal phagocytes represents a specific response that discriminates pathogenic bacteria from commensal bacteria and contributes to host defense in the intestine.
Abstract: Intestinal phagocytes transport oral antigens and promote immune tolerance, but their role in innate immune responses remains unclear. Here we report that intestinal phagocytes are anergic to Toll-like receptor ligands or commensals, but constitutively express pro-interleukin-1β (proIL-1β). Upon infection with pathogenic Salmonella or Pseudomonas, intestinal phagocytes produce mature IL-1β through the NLRC4 inflammasome, but not tumor necrosis factor or IL-6. Mice deficient in NLRC4 or IL-1 receptor on a Balb/c background were highly susceptible to orogastric but not intraperitoneal infection with Salmonella. Increased lethality was preceded by impaired expression of endothelial adhesion molecules, lower neutrophil recruitment, and poor intestinal pathogen clearance. Thus, NLRC4-dependent IL-1β production by intestinal phagocytes represents a specific response discriminating pathogenic from commensal bacteria and contributes to host defense in the intestine.

329 citations

Journal ArticleDOI
TL;DR: Better understanding of DC immunobiology in cancer is pivotal for designing novel or improved therapeutic approaches that will allow proper functioning of DCs in patients with cancer.
Abstract: The complexity of the tumor immunoenvironment is underscored by the emergence and discovery of different subsets of immune effectors and regulatory cells. Tumor-induced polarization of immune cell differentiation and function makes this unique environment even more intricate and variable. Dendritic cells (DCs) represent a special group of cells that display different phenotype and activity at the tumor site and exhibit differential pro-tumorigenic and anti-tumorigenic functions. DCs play a key role in inducing and maintaining the antitumor immunity, but in the tumor environment their antigen-presenting function may be lost or inefficient. DCs might be also polarized into immunosuppressive/tolerogenic regulatory DCs, which limit activity of effector T cells and support tumor growth and progression. Although various factors and signaling pathways have been described to be responsible for abnormal functioning of DCs in cancer, there are still no feasible therapeutic modalities available for preventing or reversing DC malfunction in tumor-bearing hosts. Thus, better understanding of DC immunobiology in cancer is pivotal for designing novel or improved therapeutic approaches that will allow proper functioning of DCs in patients with cancer.

308 citations


Cites background from "Dendritic cell control of tolerogen..."

  • ...However, even in multiple environmental milieus, the various DC subsets often share the ability to stimulate T cell proliferation or induce their unresponsiveness (3-5)....

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  • ...Immature DCs express low levels of MHC and co-stimulatory molecules and unable to efficiently activate T cells, although their endocytic potential is high (3-5)....

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  • ...It was shown that cDC, including tissue-resident DCs, migratory DCs and inflammatory DCs might exhibit immunosuppressive properties under certain circumstances or in immature stage (3-5)....

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References
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Journal ArticleDOI
TL;DR: Recent advances that have been made by research into the role of TLR biology in host defense and disease are described.
Abstract: The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.

7,494 citations


"Dendritic cell control of tolerogen..." refers background in this paper

  • ...In general, TLR-9-activation of DCs promotes Th1 responses (113)....

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Journal ArticleDOI
19 Mar 2010-Cell
TL;DR: The role of PRRs, their signaling pathways, and how they control inflammatory responses are discussed.

6,987 citations


"Dendritic cell control of tolerogen..." refers background in this paper

  • ...The innate immune system relies on a diverse array of receptors that can sense components of pathogens (92, 93)....

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Journal ArticleDOI
TL;DR: Findings that have advanced the understanding of IL-10 and its receptor are highlighted, as well as its in vivo function in health and disease.
Abstract: Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.

6,308 citations


"Dendritic cell control of tolerogen..." refers background in this paper

  • ...Furthermore, anti-inflammatory cytokines such IL-10 produced by DCs play a critical role in establishing chronic infection (274)....

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Journal ArticleDOI
TL;DR: The origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit are discussed.
Abstract: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses. These cells constitute a unique component of the immune system that regulates immune responses in healthy individuals and in the context of various diseases. In this Review, we discuss the origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit.

5,811 citations


"Dendritic cell control of tolerogen..." refers background in this paper

  • ...These cells may augment the immunosuppressive effects of tolerogenic DCs (203)....

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Journal ArticleDOI
Hans Clevers1
03 Nov 2006-Cell
TL;DR: A remarkable interdisciplinary effort has unraveled the WNT (Wingless and INT-1) signal transduction cascade over the last two decades, finding that Germline mutations in the Wnt pathway cause several hereditary diseases, and somatic mutations are associated with cancer of the intestine and a variety of other tissues.

5,042 citations