Monocyte-derived dendritic cells activated by bacteria or by bacteria-stimulated epithelial cells are functionally different

AbstractDendritic cells (DCs) are able to open the tight junctions between adjacent epithelial cells (ECs) and to take up both invasive and noninvasive bacteria directly from the intestinal lumen. In this study, we describe a tight cross talk between ECs and human monocyte-derived DCs (MoDCs) in bacterial handling across epithelial monolayers. We show that the release of proinflammatory mediators by ECs in response to bacteria is dependent on bacterial invasiveness and on the presence of flagella. This correlates with the capacity of EC-derived factors to modulate MoDC function. MoDCs incubated with supernatants of bacteria-treated ECs are “noninflammatory” as they release interleukin-10 (IL-10) but not IL-12 and can drive only T helper (Th)-2 type T cells. Moreover, noninflammatory MoDCs release chemokines aimed at recruiting Th2 and T-regulatory cells. In contrast, when MoDCs are incubated with ECs and bacteria in a transwell coculture system, and can contact directly the bacteria across stimulated EC monolayers, they are more inflammatory as they release IL-12 and IL-10 and induce both Th1 and Th2 responses. These results suggest that ECs are not simply a barrier to bacteria entering via the oral route, but they actively influence the activating properties of DCs. (Blood. 2005;106:2818-2826)

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Infection of Human Dendritic Cells with a Mycobacterium tuberculosis sigE Mutant Stimulates Production of High Levels of Interleukin-10 but Low Levels of CXCL10: Impact on the T-Cell Response

Infection and Immunity ◽

10.1128/iai.01687-05 ◽

2006 ◽

Vol 74 (6) ◽

pp. 3296-3304 ◽

Cited By ~ 19

Author(s):

Elena Giacomini ◽

Ambar Sotolongo ◽

Elisabetta Iona ◽

Martina Severa ◽

Maria Elena Remoli ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Mycobacterium Tuberculosis ◽

Human Monocyte ◽

Interleukin 10 ◽

T Cell Response ◽

Interleukin 12 ◽

Necrosis Factor Alpha ◽

Effector Cells ◽

Human Dendritic Cells

ABSTRACT The Mycobacterium tuberculosis genome encodes 13 sigma factors. We have previously shown that mutations in some of these transcriptional activators render M. tuberculosis sensitive to various environmental stresses and can attenuate the virulence phenotype. In this work, we focused on extracytoplasmic factor σE and studied the effects induced by the deletion of its structural gene (sigE) in the infection of human monocyte-derived dendritic cells (MDDC). We found that the wild-type M. tuberculosis strain (H37Rv), the sigE mutant (ST28), and the complemented strain (ST29) were able to infect dendritic cells (DC) to similar extents, although at 4 days postinfection a reduced ability to grow inside MDDC was observed for the sigE mutant ST28. After mycobacterium capture, the majority of MDDC underwent full maturation and expressed both inflammatory cytokines, such as tumor necrosis factor alpha, and the regulatory cytokines interleukin-12 (IL-12), IL-18, and beta interferon (IFN-β). Conversely, a higher level of production of IL-10 was observed in ST28-infected MDDC compared to H37Rv- or ST29-infected cell results. However, in spite of the presence of IL-10, supernatants from ST28-infected DC induced IFN-γ production by T cells similarly to those from H37Rv-infected DC culture. On the other hand, IL-10 impaired CXCL10 production in sigE mutant-infected DC and, indeed, its neutralization restored CXCL10 secretion. In line with these results, supernatants from ST28-infected cells showed a decreased capability to recruit CXCR3+ CD4+ T cells compared to those obtained from H37Rv-infected DC culture. Thus, our findings suggest that the sigE mutant-induced secretion of IL-10 inhibits CXCL10 expression and, in turn, the recruitment of activated-effector cells involved in the formation of granulomas.

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CCL18 differentiates dendritic cells in tolerogenic cells able to prime regulatory T cells in healthy subjects

Blood ◽

10.1182/blood-2011-02-338780 ◽

2011 ◽

Vol 118 (13) ◽

pp. 3549-3558 ◽

Cited By ~ 39

Author(s):

Imane Azzaoui ◽

Saliha Ait Yahia ◽

Ying Chang ◽

Han Vorng ◽

Olivier Morales ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Mhc Class Ii ◽

Healthy Subjects ◽

T Regulatory Cells ◽

Allergic Diseases ◽

Interleukin 10 ◽

Macrophage Colony ◽

Human Dendritic Cells ◽

Tolerogenic Dcs

Abstract The aim of this study was to evaluate the nonchemotactic function of CCL18 on human dendritic cells (DCs). In different protocols of DC differentiation, CCL18 was highly produced, suggesting that it may constitute a mandatory mediator of the differentiation process. Differentiation of monocytes from healthy subjects in the presence of granulocyte-macrophage colony-stimulating factor and CCL18 led to the development of DCs with a semimature phenotype, with intermediate levels of costimulatory and MHC class II molecules, increased CCR7 expression, which induced, in coculture with allogenic naive T cells, an increase in IL-10 production. The generated T cells were able to suppress the proliferation of effector CD4+CD25− cells, through a cytokine-dependent mechanism, and exhibited characteristics of type 1 T regulatory cells. The generation of tolerogenic DCs by CCL18 was dependent on the production of indoleamine 2,3-dioxigenase through an interleukin-10-mediated mechanism. Surprisingly, when DCs originated from allergic patients, the tolerogenic effect of CCL18 was lost in relation with a decreased binding of CCL18 to its putative receptor. This study is the first to define a chemokine able to generate tolerogenic DCs. However, this function was absent in allergic donors and may participate to the decreased tolerance observed in allergic diseases.

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Plasmacytoid dendritic cells prime IL-10–producing T regulatory cells by inducible costimulator ligand

Journal of Experimental Medicine ◽

10.1084/jem.20061660 ◽

2007 ◽

Vol 204 (1) ◽

pp. 105-115 ◽

Cited By ~ 435

Author(s):

Tomoki Ito ◽

Maria Yang ◽

Yui-Hsi Wang ◽

Roberto Lande ◽

Josh Gregorio ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

T Regulatory Cells ◽

Interleukin 10 ◽

Regulatory Cells ◽

Myeloid Dendritic Cells ◽

Cell Responses ◽

Inducible Costimulator ◽

Th2 Differentiation

Although there is evidence for distinct roles of myeloid dendritic cells (DCs [mDCs]) and plasmacytoid pre-DCs (pDCs) in regulating T cell–mediated adaptive immunity, the concept of functional DC subsets has been questioned because of the lack of a molecular mechanism to explain these differences. In this study, we provide direct evidence that maturing mDCs and pDCs express different sets of molecules for T cell priming. Although both maturing mDCs and pDCs upregulate the expression of CD80 and CD86, only pDCs upregulate the expression of inducible costimulator ligand (ICOS-L) and maintain high expression levels upon differentiation into mature DCs. High ICOS-L expression endows maturing pDCs with the ability to induce the differentiation of naive CD4 T cells to produce interleukin-10 (IL-10) but not the T helper (Th)2 cytokines IL-4, -5, and -13. These IL-10–producing T cells are T regulatory cells, and their generation by ICOS-L is independent of pDC-driven Th1 and Th2 differentiation, although, in the later condition, some contribution from endogenous IL-4 cannot be completely ruled out. Thus, in contrast to mDCs, pDCs are poised to express ICOS-L upon maturation, which leads to the generation of IL-10–producing T regulatory cells. Our findings demonstrate that mDC and pDCs are intrinsically different in the expression of costimulatory molecules that drive distinct types of T cell responses.

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Human monocyte-derived dendritic cells produce macrophage colony-stimulating factor: enhancement of c-fms expression by interleukin-10

European Journal of Immunology ◽

10.1002/(sici)1521-4141(199808)28:08<2283::aid-immu2283>3.0.co;2-x ◽

1998 ◽

Vol 28 (8) ◽

pp. 2283-2288 ◽

Cited By ~ 19

Author(s):

Claudia Rieser ◽

Reinhold Ramoner ◽

Günther Böck ◽

Yashwant M. Deo ◽

Lorenz Höltl ◽

...

Keyword(s):

Dendritic Cells ◽

Human Monocyte ◽

Interleukin 10 ◽

Colony Stimulating Factor ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

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Giardia duodenalis Arginine Deiminase Modulates the Phenotype and Cytokine Secretion of Human Dendritic Cells by Depletion of Arginine and Formation of Ammonia

Infection and Immunity ◽

10.1128/iai.00004-13 ◽

2013 ◽

Vol 81 (7) ◽

pp. 2309-2317 ◽

Cited By ~ 30

Author(s):

Stefanie Banik ◽

Pablo Renner Viveros ◽

Frank Seeber ◽

Christian Klotz ◽

Ralf Ignatius ◽

...

Keyword(s):

Dendritic Cells ◽

Critical Role ◽

Giardia Duodenalis ◽

Human Monocyte ◽

Interleukin 10 ◽

Arginine Deiminase ◽

Infection Model ◽

Reaction Products ◽

Necrosis Factor Alpha ◽

Content Type

ABSTRACTDepletion of arginine is a recognized strategy that pathogens use to evade immune effector mechanisms. Depletion depends on microbial enzymes such as arginases, which are considered virulence factors. The effect is mostly interpreted as being a consequence of successful competition with host enzymes for the substrate. However, both arginases and arginine deiminases (ADI) have been associated with pathogen virulence. Both deplete arginine, but their reaction products differ. An ADI has been implicated in the virulence ofGiardia duodenalis, an intestinal parasite that infects humans and animals, causing significant morbidity. Dendritic cells (DC) play a critical role in host defense and also in a murineG. duodenalisinfection model. The functional properties of these innate immune cells depend on the milieu in which they are activated. Here, the dependence of the response of these cells on arginine was studied by usingGiardiaADI and lipopolysaccharide-stimulated human monocyte-derived DC. Arginine depletion by ADI significantly increased tumor necrosis factor alpha and decreased interleukin-10 (IL-10) and IL-12p40 secretion. It also reduced the upregulation of surface CD83 and CD86 molecules, which are involved in cell-cell interactions. Arginine depletion also reduced the phosphorylation of S6 kinase in DC, suggesting the involvement of the mammalian target of rapamycin signaling pathway. The changes were due to arginine depletion and the formation of reaction products, in particular, ammonium ions. Comparison of NH4+and urea revealed distinct immunomodulatory activities of these products of deiminases and arginases, respectively. The data suggest that a better understanding of the role of arginine-depleting pathogen enzymes for immune evasion will have to take enzyme class and reaction products into consideration.

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Gene Transfer Early in Gestation Results in Transduction of Key Cellular Mediators of Both Central and Peripheral Immune Tolerance.

Blood ◽

10.1182/blood.v110.11.2585.2585 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2585-2585

Author(s):

Evan Colletti ◽

Sean Lindsted ◽

Paul Park ◽

Graça Almeida-Porada ◽

Christopher D. Porada

Keyword(s):

Gene Therapy ◽

Dendritic Cells ◽

Gene Transfer ◽

Epithelial Cells ◽

Immune Tolerance ◽

T Regulatory Cells ◽

Peripheral Tolerance ◽

Thymic Epithelial Cells ◽

Regulatory Cells ◽

Fetal Sheep

Abstract We have previously reported that the direct intraperitoneal (IP) injection of murine stem cell virus (MSCV)-based retroviral vectors into preimmune fetal sheep results in the induction of stable long-term immune tolerance to an antigenic transgene product that enables post-natal antigen boosting without eliciting an immune response. These results suggested that in utero gene therapy (IUGT) may be an ideal approach for treating diseases such as the hemophilias, in which post-natal attempts at both gene therapy and protein replacement therapy have often been thwarted by the formation of immune inhibitors. In the present studies, we performed experiments to delineate the mechanism of the observed immune tolerance following IUGT and to define the optimal window during gestation when gene transfer should be performed to ensure induction of transgene immune tolerance. To this end, we performed IUGT on fetal sheep at various gestational ages (55–110 days of gestation; term: 150 days). At 30 days post-IUGT, sheep were euthanized and thymic cryosections analyzed by immunohistochemistry using an antibody specific to the vector-encoded NeoR transgene product (NPT) and either a pan-cytokeratin antibody to label thymic epithelial cells, or an anti-CD45 antibody to label thymocytes. We determined that thymic tissue is in fact transduced in the majority of animals following IUGT regardless of the age at which IUGT is performed. Importantly, however, efficient transduction of thymic epithelial cells that are thought to be one of the key cell types responsible for presentation of self-antigen during T cell thymic selection only occurred if the gene transfer was performed prior to 72 days of gestation (term: 150 days). If IUGT was performed at day 72 or later, transduction was limited to predominantly thymocytes. These results suggest that IUGT may only result in successful induction of central immune tolerance if performed prior to 72 days of gestation in this model. These ongoing studies have also revealed that epithelial-like thymic stromal lymphopoietin (TSLP)+ cells comprising the Hassall’s corpuscles are also transduced if IUGT is performed early in gestation (prior to 72 days of gestation), but not if it is performed after that point. Since recent studies have shown that one of the main functions of the Hassall’s corpuscles is to instruct dendritic cells to induce the formation of CD4+CD25+ T-regulatory cells in the thymus, we performed FACS analysis on the peripheral blood of animals that received IUGT at varying gestational ages, focusing on subtypes of immune effector cells. These analyses revealed that animals that received IUGT early in gestation (prior to 72 days) have significantly higher percentages of CD4+CD25+ cells within their periphery than do animals transduced later in gestation. This finding is particularly interesting, given that CD4+CD25+ cells are thought to be T-regulatory cells that are involved in maintenance of peripheral tolerance. In conclusion, we have shown that by performing IUGT early in gestation, one can take advantage of multiple tolerogenic avenues present in the fetus, transducing both thymic epithelial cells which may promote induction of central immune tolerance and cells of Hassall’s corpuscles, which can then in turn lead to the instruction of dendritic cells to induce the formation of T-regulatory cells that can help maintain peripheral immune tolerance to the transgene products.

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Bordetella pertussis-Infected Human Monocyte-Derived Dendritic Cells Undergo Maturation and Induce Th1 Polarization and Interleukin-23 Expression

Infection and Immunity ◽

10.1128/iai.73.3.1590-1597.2005 ◽

2005 ◽

Vol 73 (3) ◽

pp. 1590-1597 ◽

Cited By ~ 43

Author(s):

Giorgio Fedele ◽

Paola Stefanelli ◽

Fabiana Spensieri ◽

Cecilia Fazio ◽

Paola Mastrantonio ◽

...

Keyword(s):

Dendritic Cells ◽

Bordetella Pertussis ◽

Whooping Cough ◽

Natural Infection ◽

Human Monocyte ◽

Cell Types ◽

Interleukin 10 ◽

Cell Mediated Immunity ◽

T Helper 1 ◽

Cell Functions

ABSTRACT Bordetella pertussis, the causative agent of whooping cough, is internalized by several cell types, including epithelial cells, monocytes, and neutrophils. Although its ability to survive intracellularly is still debated, it has been proven that cell-mediated immunity (CMI) plays a pivotal role in protection. In this study we aimed to clarify the interaction of B. pertussis with human monocyte-derived dendritic cells (MDDC), evaluating the ability of the bacterium to enter MDDC, to survive intracellularly, to interfere with the maturation process and functional activities, and to influence the host immune responses. The results obtained showed that B. pertussis had a low capability to be internalized by—and to survive in—MDDC. Upon contact with the bacteria, immature MDDC were induced to undergo phenotypic maturation and acquired antigen-presenting-cell functions. Despite the high levels of interleukin-10 (IL-10) and the barely detectable levels of IL-12 induced by B. pertussis, the bacterium induced maturation of MDDC and T helper 1 (Th1) polarized effector cells. Gene expression analysis of the IL-12 cytokine family clearly demonstrated that B. pertussis induced high levels of the p40 and p19 subunits of IL-23 yet failed to induce the expression of the p35 subunit of IL-12. Overall our findings show that B. pertussis, even if it survives only briefly in MDDC, promotes the synthesis of IL-23, a newly discovered Th1 polarizing cytokine. A Th1-oriented immune response is thus allowed, relevant in the induction of an adequate CMI response, and typical of protection induced by natural infection or vaccination with whole-cell vaccines.

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