CCL18 differentiates dendritic cells in tolerogenic cells able to prime regulatory T cells in healthy subjects (original) (raw)
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Unique Regulation of CCL18 Production by Maturing Dendritic Cells
The Journal of Immunology, 2003
Dendritic cells (DC) orchestrate the trafficking of lymphocytes by secreting chemokines with different specificity and function. Chemokines are produced at higher levels by mature DC. This study shows that CCL18 is one of the most abundant chemokines produced by immature DC. In contrast to all other chemokines investigated to date, CCL18 was selectively down-regulated during the maturation process induced by LPS, TNF, CD40 ligand, Staphylococcus aureus Cowan I, Candida albicans, and influenza virus. IL-10 and vitamin D 3 , two known inhibitors of DC differentiation and function, strongly promoted CCL18 secretion, whereas IFN-␥, a costimulator of DC function, inhibited its production. IL-10 also induced CCL18 secretion in blood myeloid DC. No CCL18 secretion was observed in blood plasmacytoid DC. The opposite pattern of regulation was observed for CCL20, a prototypic inflammatory chemokine. CCL18 was found to be a chemotactic factor for immature DC. Therefore, CCL18 may act as a chemotactic signal that promotes the colocalization of immature DC with naive T lymphocytes in an IL-10-dominated environment with the consequent generation of T regulatory cells. These characteristics suggest that CCL18 may be part of an inhibitory pathway devoted to limiting the generation of specific immune responses at peripheral sites.
International Immunology, 2007
The factors that influence the functionality of human CD4 + CD25 + regulatory T cells are not well understood. We sought to characterize the effects of dendritic cells (DCs) on the in vitro regulatory activity of CD4 + CD25 + T cells obtained from peripheral blood of healthy human donors. Flow cytometry showed that a higher proportion of CD4 + CD25 +(High) T cells expressed surface glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) and CTL-associated antigen 4 than CD4 + CD25 À or CD4 + CD25 +(Med-low) T cells. Intracellular Foxp3 was equivalently expressed on CD4 + CD25 +(All) , CD4 + CD25 +(High) , CD4 + CD25 +(Med-low) and CD4 + CD25 À T cell populations, irrespective of GITR and CTL-associated antigen 4 expression. CD4 + CD25 + T cells were isolated and then cultured in vitro with CD4 + CD25 À responder T cells and stimulated with anti-CD3 antibodies, and immature dendritic cells (iDCs), mature dendritic cells (mDCs), PBMCs or PBMCs plus anti-CD28 antibodies to provide co-stimulation. In addition, secretion of the T h 1 cytokine IFN-g, IL-2 and the immunoregulatory cytokines, IL-10 and transforming growth factor (TGF)-b, were also assessed in these cultures. We found that iDCs and mDCs were capable of reversing the suppression of proliferation mediated by CD4 + CD25 + regulatory T cells. However, the reversal of suppression by DCs was not dependent upon the increase of IFN-g and IL-2 production or inhibition of IL-10 and/or TGF-b production. Therefore, DCs are able to reverse the suppressive effect of regulatory T cells independent of cytokine production. These results suggest for the first time that human DCs possess unique abilities which allow them to influence the functions of regulatory T cells in order to provide fine-tuning in the regulation of T cell responses.
American Journal of Immunology, 2005
IL-10 is a multifunctional cytokine with known inhibitory effect on DC maturation. In the present study, we show that the presence of IL-10 during the first 6 days of maturation of Mo-DC has severe effects on the phenotype with IL-10 treated Mo-DC retaining a high expression of factors involved in antigen uptake and having low expression of costimulatory factors and MHC II. The effect of IL-10 on DC maturation is further characterized by a comprehensive investigation of the expression profile of 12500 genes using GeneArrays and comparing the data for IL-10 treated and untreated Mo-DC at day 6 and 8 with monocytes and macrophages. The data is confirmed with semi-quantitative RT-PCR. We find that the transcriptional pattern of IL-10 treated Mo-DC at day 6 and day 8 is distinct from both untreated Mo-DC and macrophages. IL-10 induces the expression of genes coding for CCL18, ILT3, ILT4 and TGFβ while inhibiting the expression of IL-12 p40 mRNA, and genes coding for CCL17, CCL19 and CCL22 suggesting a likely effect of IL-10 on Mo-DC maturation to be the generation of tolerogenic Mo-DC.
Journal of Experimental Medicine, 2000
The functional properties of dendritic cells (DCs) are strictly dependent on their maturational state. To analyze the influence of the maturational state of DCs on priming and differentiation of T cells, immature CD83 Ϫ and mature CD83 ϩ human DCs were used for stimulation of naive, allogeneic CD4 ϩ T cells. Repetitive stimulation with mature DCs resulted in a strong expansion of alloreactive T cells and the exclusive development of T helper type 1 (Th1) cells. In contrast, after repetitive stimulation with immature DCs the alloreactive T cells showed an irreversibly inhibited proliferation that could not be restored by restimulation with mature DCs or peripheral blood mononuclear cells, or by the addition of interleukin (IL)-2. Only stimulation of T cells with mature DCs resulted in an upregulation of CD154, CD69, and CD70, whereas T cells activated with immature DCs showed an early upregulation of the negative regulator cytotoxic T lymphocyte-associated molecule 4 (CTLA-4). These T cells lost their ability to produce interferon ␥ , IL-2, or IL-4 after several stimulations with immature DCs and differentiated into nonproliferating, IL-10-producing T cells. Furthermore, in coculture experiments these T cells inhibited the antigen-driven proliferation of Th1 cells in a contact-and dose-dependent, but antigen-nonspecific manner. These data show that immature and mature DCs induce different types of T cell responses: inflammatory Th1 cells are induced by mature DCs, and IL-10-producing T cell regulatory 1-like cells by immature DCs.
The Journal of Immunology, 2010
IL-10-differentiated dendritic cells (DC10) induce allergen tolerance in asthmatic mice, during which their lung Th2 effector T cells (Teffs) are displaced by activated CD4 + CD25 hi Foxp3 + T cells. Intestinal DCs promote oral tolerance by inducing Ag-naive T cells to differentiate into CD4 + CD25 + Foxp3 + regulatory T cells (Tregs), but whether DCs can induce Teffs to differentiate into Tregs remains uncertain. In this study, we addressed this question in OVA-asthmatic mice that were treated with DC10. OVA-presenting DC10 treatment maximally activated lung Tregs in these animals at 3 wk posttreatment, as determined by upregulation of activation markers (ICOS, programmed cell death-1, glucocorticoid-induced TNFR-related protein, LAG3, and CTLA-4) and in functional assays. This in vitro regulatory activity was ‡90% reduced by treatment with anti-IL-10 but not anti-TGF-b Abs. In parallel cultures, OVA-but not house dust mite (HDM)-presenting DC10 induced 43% of CFSE-labeled CD25 2/lo Foxp3 2 Teffs from asthmatic OVA-TCR transgenic mice to differentiate into tolerogenic CD25 hi Foxp3 + Tregs. We recapitulated this in vivo using OVA-asthmatic mice that were coinjected with OVA-or HDM-presenting DC10 (i.p.) and CFSE-labeled CD4 + CD25-/lo Foxp3 2 Teffs (i.v.) from the lungs of asthmatic DO11.10 mice. From 7 to 21% of the activated (i.e., dividing) DO11.10 Teffs that were recovered from the lungs, lung-draining lymph nodes, or spleens of the OVA-DC10 recipients had differentiated into CD4 + CD25 hi Foxp3 + Tregs, whereas no CFSE-positive Tregs were recovered from the HDM-DC10-treated animals. These data indicate that DC10 treatments induce tolerance at least in part by inducing Teffs to differentiate into CD4 + CD25 hi Foxp3 + Tregs.
CCR2 Plays a Critical Role in Dendritic Cell Maturation: Possible Role of CCL2 and NF-κB
The Journal of …, 2010
We postulated that CCR2-driven activation of the transcription factor NF-κB plays a critical role in dendritic cell (DC) maturation (e.g., migration, costimulation, and IL-12p70 production), necessary for the generation of protective immune responses against the intracellular pathogen Leishmania major. Supporting this notion, we found that CCR2, its ligand CCL2, and NF-κB were required for CCL19 production and adequate Langerhans cell (LC) migration both ex vivo and in vivo. Furthermore, a role for CCR2 in upregulating costimulatory molecules was indicated by the reduced expression of CD80, CD86, and CD40 in Ccr2−/− bone marrow-derived dendritic cells (BMDCs) compared with wild-type (WT) BMDCs. Four lines of evidence suggested that CCR2 plays a critical role in the induction of protective immunity against L. major by regulating IL-12p70 production and migration of DC populations such as LCs. First, compared with WT, Ccr2−/− lymph node cells, splenocytes, BMDCs, and LCs produced lower levels of IL-12p70 following stimulation with LPS/IFN-γ or L. major. Second, a reduced number of LCs carried L. major from the skin to the draining lymph nodes in Ccr2−/− mice compared with WT mice. Third, early treatment with exogenous IL-12 reversed the susceptibility to L. major infection in Ccr2−/− mice. Finally, disruption of IL-12p70 in radioresistant cells, such as LCs, but not in BMDCs resulted in the inability to mount a fully protective immune response in bone marrow chimeric mice. Collectively, our data point to an important role for CCR2-driven activation of NF-κB in the regulation of DC/LC maturation processes that regulate protective immunity against intracellular pathogens.
Dendritic cells as a major source of macrophage-derived chemokine/CCL22in vitro andin vivo
European Journal of Immunology, 2001
Macrophage-derived chemokine (MDC)/CCL22 is a CC chemokine active on dendritic cells (DC), NK cells and Th2 lymphocytes. The present study was aimed at comprehensively investigating MDC production in vitro and in vivo. DC were the most potent producers of MDC among leukocytes tested. Endothelial cells did not produce MDC under a variety of conditions. Signals that induce maturation (lipopolysaccharide, IL-1, TNF, CD40 ligand, recognition of bacteria and yeast) dramatically augmented MDC production, and dexamethasone and vitamin D3 blocked it. Prostaglandin E 2 , which blocked the acquisition of IL-12 production and the capacity to promote Th1 generation, did not affect MDC production. Using mass spectrometry-based techniques, DC supernatants were found to contain Nterminally truncated forms of MDC [MDC(3-69), MDC(5-69) and MD(C7-69)] as well as the full-length molecule. In vivo, CD1a + , CD83 + , MDC + DC were found in reactive lymph nodes, and in Langerhans' cell histiocytosis. Skin lesions of atopic dermatitis patients showed that CD1a + or CD1b + DC, and DC with a CD83 + phenotype were responsible for MDC production in this Th2-oriented disorder. Thus, DC are the predominant source of MDC in vitro and in vivo under a variety of experimental and clinical conditions. Processing of MDC to MDC(3-69) and shorter forms which do not recognize CCR4 is likely to represent a feedback mechanism of negative regulation.