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DC Function (dc + function)

Distribution by Scientific Domains

Medical Sciences	90%

Selected Abstracts

Dendritic cells derived from TBP-2-deficient mice are defective in inducing T cell responses

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2008
Aoi Son
Abstract Thioredoxin-binding protein-2 (TBP-2), also known as vitamin,D3-up-regulated protein,1 (VDUP1), was identified as an endogenous molecule interacting with thioredoxin (TRX). Here, we show that dendritic cells (DC) derived from TBP-2-deficient mice are defective in the function of T cell activation. To compare TBP-2,/, DC function with wild-type (WT) DC, we stimulated DC with lipopolysaccharide (LPS). Although TBP-2,/, DC and WT DC expressed comparable levels of MHC class,II and costimulatory molecules such as CD40, CD80 and CD86, the IL-12p40, IL-12p70 and IL-6 productions of TBP-2,/, DC were attenuated. In a mixed leukocyte reaction (MLR), the concentrations of IL-2, IFN-,, IL-4 and IL-10 in the culture supernatant of MLR with TBP-2,/, DC were significantly lower than those in the cultures with WT DC. In MLR also, as with LPS stimulation, IL-12p40 and IL-12p70 production from TBP-2,/, DC was less than that from WT DC. Proliferation of T cells cultured with TBP-2,/, DC was poorer than that with WT DC. Invivo delayed-type hypersensitivity responses in TBP-2,/, mice immunized with ovalbumin were significantly reduced compared to WT mice. These results indicate that TBP-2 plays a crucial role in DC to induce T cell responses. [source]

Impairment of dendritic cell function by excretory-secretory products: A potential mechanism for nematode-induced immunosuppression

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2007
Mariela Segura
Abstract To determine whether helminth-derived products modulate dendritic cell (DC) function, we investigated the effects of excretory-secretory products (ES) and adult worm homogenate (AWH) derived from the gastrointestinal nematode Heligmosomoides polygyrus (Hp) on murine bone marrow-derived DC (BMDC). Compared to the TLR9 ligand CpG, Hp-derived products alone failed to induce DC activation. ES, but not AWH, inhibited BMDC cytokine and chemokine production and co-stimulatory molecule expression (CD40, CD86 and MHC class,II) induced by TLR ligation. TLR ligand-independent, PMA-induced DC activation was unaffected by ES. Recipients of ES-treated BMDC pulsed with OVA had suppressed Ab responses in vivo, irrespective of the Th1 or Th2 isotype affiliation, compared to recipients of control OVA-pulsed BMDC. Importantly, suppression occurred even in the presence of the potent type,1 adjuvant CpG. In contrast to untreated OVA-pulsed BMDC, ES-treated BMDC pulsed with OVA had reduced co-stimulatory molecule and cytokine expression. CD4+CD25+Foxp3, T cells, which secreted high IL-10 levels, were generated in co-cultures of OT-II OVA-specific TCR-transgenic CD4+ T cells and ES-treated BMDC. These IL-10-secreting T cells suppressed effector CD4+ T cell proliferation and IFN-, production, the latter effect mediated by an IL-10-dependent mechanism. Together, these results demonstrate that nematode ES impaired DC function and suppressed both Th1 and Th2 adaptive immune responses possibly by inducing regulatory T cells. [source]

Turning it on and off: regulation of dendritic cell function in Toxoplasma gondii infection

IMMUNOLOGICAL REVIEWS, Issue 1 2004
Julio Aliberti
Summary:, Because of its intrinsic virulence, Toxoplasma gondii induces a potent interleukin-12 (IL-12)-dependent cell-mediated immune response that shuts down the growth of the replicative tachyzoite stage, thus promoting host survival and successful transmission through predation. At the same time, this response must be tightly controlled to prevent lethality due to cytokine-mediated immunopathology. Evidence accumulated in recent years suggests that dendritic cells (DCs) play a major role in the initiation of IL-12-driven host resistance and that IL-12 synthesis by DCs is carefully regulated to avoid overproduction. In addition, this work has revealed a critical role for DCs in determining the highly polarized T-helper 1 (Th1)-type response triggered by the parasite. In this review, we summarize our current understanding of how DC function is initiated by Toxoplasma and how parasite-primed DCs drive Th1 effector choice. In addition, we discuss recent findings concerning the pathways responsible for endogenous regulation of DC IL-12 production during T. gondii infection. [source]

Apoptotic cells induce dendritic cell-mediated suppression via interferon-,-induced IDO

IMMUNOLOGY, Issue 1 2008
Charlotte A. Williams
Summary Dendritic cells (DC) are sensitive to their local environment and are affected by proximal cell death. This study investigated the modulatory effect of cell death on DC function. Monocyte-derived DC exposed to apoptotic Jurkat or primary T cells failed to induce phenotypic maturation of the DC and were unable to support CD4+ allogeneic T-cell proliferation compared with DC exposed to lipopolysaccharide (LPS) or necrotic cells. Apoptotic cells coincubated with LPS- or necrotic cell-induced mature DC significantly suppressed CD80, CD86 and CD83 and attenuated LPS-induced CD4+ T-cell proliferation. Reduced levels of interleukin-12 (IL-12), IL-10, IL-6, tumour necrosis factor-, and interferon-, (IFN-,) were found to be concomitant with the suppressive activity of apoptotic cells upon DC. Furthermore, intracellular staining confirmed IFN-, expression by DC in association with apoptotic environments. The specific generation of IFN-, by DC within apoptotic environments is suggestive of an anti-inflammatory role by the induction of indoleamine 2,3-dioxygenase (IDO). Both neutralization of IFN-, and IDO blockade demonstrated a role for IFN-, and IDO in the suppression of CD4+ T cells. Moreover, we demonstrate that IDO expression within the DC was found to be IFN-,-dependent. Blocking transforming growth factor-, (TGF-,) also produced a partial release in T-cell proliferation. Our study strongly suggests that apoptosis-induced DC suppression is not an immunological null event and two prime mediators underpinning these functional effects are IFN-,-induced IDO and TGF-,. [source]

Administration of dendritic cells modified by RNA interference prolongs cardiac allograft survival

MICROSURGERY, Issue 4 2007
Jianbin Xiang M.D.
Systemic administration of immature donor-dendritic cells (DC) that are deficient in co-stimulatory molecules delays the onset of allograft rejection. However, it is not easy to control culture condition and guarantee that the administered DC are in the immature stages, which obviously affects their therapeutic effect. In this study, we attempted to inhibit expression of CD86 on DC using an RNA interference technology. The function of CD86low DC was determined by the influence on their capacity to stimulate T cell proliferation and by the effect of DC systemic administration on survival of cardiac allografts. CD86low DC stimulated low T cell proliferative responses in vitro and administration of CD86low DC prolonged survival of heart allografts in vivo. These results suggest that RNA interference is a useful approach to modify DC function, which has potentials for clinical application. © 2007 Wiley-Liss, Inc. Microsurgery 2007. [source]

MyD88 and IFN-,, differentially control maturation of bystander but not Salmonella -associated dendritic cells or CD11cintCD11b+ cells during infection

CELLULAR MICROBIOLOGY, Issue 7 2008
Miguel A. Tam
Summary The interface between dendritic cells (DCs) and T cells is critical to elicit effective immunity against pathogens. The maturation state of DCs determines the quality of the interaction and governs the type of response. DCs can be matured directly through activating Toll-like receptors (TLRs) or indirectly by cytokines. We explore the role of the TLR adaptor MyD88 on DC maturation during Salmonella infection. Using Salmonella expressing GFP, we also examine the phenotype and function of bacteria-associated DCs matured in the absence of bacteria-mediated TLR signalling. MyD88 was required for upregulation of CD80 on DCs during infection, whereas CD86 and CD40 were upregulated independently of MyD88, although requiring a higher bacterial burden in the MLN. MyD88-independent upregulation was mediated by IFN-,, produced during infection. In infected MyD88,/,IFN-,,R,/, mice, which lack most bacteria-driven TLR signalling, indirect DC maturation was abolished. In contrast, DCs containing Salmonella upregulated co-stimulatory molecules independently of MyD88 and IFN-,,, revealing a pathway of phenotypic maturation active in infected DCs. However, despite high co-stimulatory molecule expression, Salmonella -containing DCs from MyD88,/, or MyD88,/,IFN-,,R,/, mice had a compromised capacity to activate T cells. Thus, bacterial stimulation of TLRs influences DC function at multiple levels that modulates their capacity to direct antibacterial immunity. [source]

Impaired maturation and function of dendritic cells by mycobacteria through IL-1,

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2006
Masahiko Makino Dr.
Abstract Dendritic cells (DC) are pivotal for initiation and regulation of innate and adaptive immune responses evoked by vaccination and natural infection. After infection, mycobacterial pathogens first encounter monocytes, which produce pro-inflammatory cytokines, including IL-1,, TNF-, and IL-6. The role of these cytokines in DC maturation remains incompletely understood. Here, we show that maturation of DC from monocytes was impaired by pretreatment of monocytes with low doses of IL-1,. Under these conditions, Mycobacterium leprae -infected DC failed to stimulate antigen-specific T cell responses. Expression of CD86 and CD83 and production of IL-12 in response to lipopolysaccharide and peptidoglycan were diminished. In contrast, these DC functions were not impaired by pretreatment with TNF-,, IL-6 or IL-10. When monocytes were infected with M. bovis Bacillus Calmette-Guérin, and subsequently differentiated to DC, the activity of these DC was suppressed as well. Thus, IL-1, acts at early stages of differentiation of DC and impairs biological functions of DC at later stages. Therefore, production of IL-1, by mycobacteria-infected antigen-presenting cells counteracts effective stimulation of innate and adaptive immune responses. [source]

Intestinal dendritic cells: Their role in bacterial recognition, lymphocyte homing, and intestinal inflammation

INFLAMMATORY BOWEL DISEASES, Issue 10 2010
S.C. Ng PhD
Abstract Dendritic cells (DCs) play a key role in discriminating between commensal microorganisms and potentially harmful pathogens and in maintaining the balance between tolerance and active immunity. The regulatory role of DC is of particular importance in the gut where the immune system lies in intimate contact with the highly antigenic external environment. Intestinal DC constantly survey the luminal microenvironment. They act as sentinels, acquiring antigens in peripheral tissues before migrating to secondary lymphoid organs to activate naive T cells. They are also sensors, responding to a spectrum of environmental cues by extensive differentiation or maturation. Recent studies have begun to elucidate mechanisms for functional specializations of DC in the intestine that may include the involvement of retinoic acid and transforming growth factor-,. Specialized CD103+ intestinal DC can promote the differentiation of Foxp3+ regulatory T cells via a retinoic acid-dependent process. Different DC outcomes are, in part, influenced by their exposure to microbial stimuli. Evidence is also emerging of the close interaction between bacteria, epithelial cells, and DC in the maintenance of intestinal immune homeostasis. Here we review recent advances of functionally specialized intestinal DC and their mechanisms of antigen uptake and recognition. We also discuss the interaction of DC with intestinal microbiota and their ability to orchestrate protective immunity and immune tolerance in the host. Lastly, we describe how DC functions are altered in intestinal inflammation and their emerging potential as a therapeutic target in inflammatory bowel disease. (Inflamm Bowel Dis 2010) [source]

How to outwit the enemy: dendritic cells face Salmonella,

APMIS, Issue 9 2006
Review article
Salmonella enterica serovar Typhi causes typhoid fever, a serious life-threatening systemic infection. In mice, a similar disease is caused by Salmonella enterica serovar Typhimurium. During typhoid fever, soon after attachment to the mucosal surface of the gut, bacteria come into contact with the dendritic cells (DCs). The ability to sample antigens, process and present them to na,Ðve and mature T cells, in the context of major histocompatibility complex molecules, makes DCs indispensable for mounting a specific and efficient immune response to invading pathogens. These bacteria, however, have evolved a number of mechanisms to interfere with or subvert DC functions. This review aims to describe how Salmonella clashes with dendritic cells at different stages of infection as well as the war strategies of these two opposing sides. [source]

Generation of mature dendritic cells fully capable of T helper type 1 polarization using OK-432 combined with prostaglandin E2

CANCER SCIENCE, Issue 12 2003
Marimo Sato
Dendritic cell (DC) administration appears to be a very promising approach for the immunotherapy of cancer. The results of clinical studies have suggested that the nature and the magnitude of antitumor immune responses are critically affected by DC functions, including production of T helper type 1 (Th1)-inducing cytokines, activation of T cell subsets and natural killer (NK) cells, and migration from peripheral tissues to the T cell area of the draining lymph nodes. Administration of immature DCs could fail to fully stimulate antigen-specific immune responses and might induce tolerance under some conditions. In this study, we developed a method to obtain fully mature DCs, and we compared in detail the DCs thus obtained with those obtained using a maturation stimulus termed monocyte-derived medium (MCM)-mimic, which is a mixture of recombinant cytokines and prostaglandin E2 (PGE2) mimicking the components of monocyte-conditioned medium. Using DCs derived from monocytes of advanced cancer patients in this study, we found that DCs stimulated with OK-432 alone showed phenotypes similar to those of mature DCs induced using MCM-mimic, though with better secretion of IL-6 and IL-12. However, these DCs were found to have poor migratory capacity associated with the marginal expression of CCR7. When OK-432 was combined with PGE2, the CCR7 expression and migratory capacity of DCs were significantly improved without impairing other immuno-stimulatory functions. These results suggest that stimulation with the combination of OK-432 and PGE2 could be applicable as an alternative to MCM-mimic in clinical trials which require fully matured DCs to induce Th1-type immune responses against tumor cells even in patients with advanced cancer. [source]