Naturally occurring CD1c+ human regulatory dendritic cells: Immunoregulators that are expanded in response to E. coli infection

National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China.
European Journal of Immunology (Impact Factor: 4.03). 06/2012; 42(6):1388-92. DOI: 10.1002/eji.201242632
Source: PubMed


Dendritic cells (DCs) play key roles in initiating and regulating immunity by sensing and integrating signals from a wide range of pathogens and dangers. Although much knowledge has been gained about the origins, phenotypes, and functions of mouse DC subsets, the challenge now is to translate this knowledge to the human immune system and reveal relevant biological significance in human health and disease. Considerably less is known about the phenotype and function of human DC subsets due to their rarity, the lack of distinctive markers, and limited access to human tissues. Initial studies of DCs in human blood revealed that steady-state myeloid DCs are comprised of the CD141(+) and CD1c(+) DC subsets as the equivalents to the mouse lymphoid resident CD8(+) and CD8(-) DC subsets, respectively. A new report in this issue of the European Journal of Immunology [Eur. J. Immunol. 2012. 42: 1512-1522] shows that human CD1c(+) myeloid DCs secrete IL-10 and display an immunoregulatory phenotype and function in response to Escherichia coli (E. coli). This finding adds a new element to the current understanding of human CD1c(+) DCs and reveals marked differences in human DC subsets during inflammation and microbial infection, as discussed in this Commentary.

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    • "CD1c+ mDCs in the circulation have been suggested to represent immature DCs that express CD86 and respond to microbial products rather than to inflammatory stimuli (such as tumour necrosis factor alpha) [12]. Recently, CD1c+ mDCs were described to have an immunoregulatory function in response to certain microbial triggers [16,17]. "
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    ABSTRACT: Myeloid dendritic cells (mDCs) are potent T cell-activating antigen-presenting cells that have been suggested to play a crucial role in the regulation of immune responses in many disease states, including rheumatoid arthritis (RA). Despite this, studies that have reported on the capacity of naturally occurring circulating mDCs to regulate T cell activation in RA are still lacking. This study aimed to evaluate the phenotypic and functional properties of naturally occurring CD1c (BDCA-1)+ mDCs from synovial fluid (SF) compared to those from peripheral blood (PB) of RA patients. CD1c+ mDC numbers and expression of costimulatory molecules were assessed by fluorescence-activated cell sorting (FACS) analysis in SF and PB from RA patients. Ex vivo secretion of 45 inflammatory mediators by mDCs from SF and PB of RA patients was determined by multiplex immunoassay. The capacity of mDCs from SF to activate autologous CD4+ T cells was measured. CD1c+ mDC numbers were significantly increased in SF versus PB of RA patients (mean 4.7% vs. 0.6%). mDCs from SF showed increased expression of antigen-presenting (human leukocyte antigen (HLA) class II, CD1c) and costimulatory molecules (CD80, CD86 and CD40). Numerous cytokines were equally abundantly produced by mDCs from both PB and SF (including IL-12, IL-23, IL-13, IL-21). SF mDCs secreted higher levels of interferon γ-inducible protein-10 (IP-10), monokine induced by interferon γ (MIG) and, thymus and activation-regulated chemokine (TARC), but lower macrophage-derived chemokine (MDC) levels compared to mDCs from PB. mDCs from SF displayed a strongly increased capacity to induce proliferation of CD4+ T cells associated with a strongly augmented IFNγ, IL-17, and IL-4 production. This study suggests that increased numbers of CD1c+ mDCs in SF are involved in the inflammatory cascade intra-articularly by the secretion of specific T cell-attracting chemokines and the activation of self-reactive T cells.
    Arthritis research & therapy 10/2013; 15(5):R155. DOI:10.1186/ar4338 · 3.75 Impact Factor
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    • "In response to an infectious challenge, the primary goal of the innate immune response is to rapidly clear or contain offending pathogens to prevent prolonged inflammation and sepsis [25]. The innate immune response is initiated by the recognition of bacterial ligands and activation of epithelial and resident sub-epithelial immune cells, such as mast cells[26], [27], macrophages[28] and dendritic cells[29], resulting in a rapid burst of pro-inflammatory cytokines (e.g. IL-6, IL-8, and TNF-α) and lipid-derived mediators (e.g. "
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    ABSTRACT: The clinical onset and severity of intestinal disorders in humans and animals can be profoundly impacted by early life stress. Here we investigated the impact of early weaning stress in pigs on intestinal physiology, clinical disease, and immune response to subsequent challenge with enterotoxigenic F18 E. coli (ETEC). Pigs weaned from their dam at 16 d, 18 d, and 20 d of age were given a direct oral challenge of F18 ETEC at 26 d of age. Pigs were monitored from days 0 to 4 post-infection for clinical signs of disease. On Day 4 post-ETEC challenge, ileal barrier function, histopathologic and inflammatory cytokine analysis were performed on ileal mucosa. Early weaned pigs (16 d and 18 d weaning age) exhibited a more rapid onset and severity of diarrhea and reductions in weight gain in response to ETEC challenge compared with late weaned pigs (20 d weaning age). ETEC challenge induced intestinal barrier injury in early weaned pigs, indicated by reductions in ileal transepithelial electrical resistance (TER) and elevated FD4 flux rates, in early weaned pig ileum but not in late weaned pigs. ETEC-induced marked elevations in IL-6 and IL-8, neutrophil recruitment, and mast cell activation in late-weaned pigs; these responses were attenuated in early weaned pigs. TNF levels elevated in ETEC challenged ileal mucosa from early weaned pigs but not in other weaning age groups. These data demonstrate the early weaning stress can profoundly alter subsequent immune and physiology responses and clinical outcomes to subsequent infectious pathogen challenge. Given the link between early life stress and gastrointestinal diseases of animals and humans, a more fundamental understanding of the mechanisms by which early life stress impacts subsequent pathophysiologic intestinal responses has implications for the prevention and management of important GI disorders in humans and animals.
    PLoS ONE 04/2013; 8(4):e59838. DOI:10.1371/journal.pone.0059838 · 3.23 Impact Factor
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    ABSTRACT: Three major functional subsets of dendritic cells (DCs) have been described in the tumor microenvironment in patients with cancer and tumor-bearing animals: (i) conventional DCs with intact antigen-presenting capabilities, (ii) functionally defective DCs with decreased motility and low ability to uptake, process and present antigens or produce cytokines and (iii) regulatory DCs with high capacity to suppress T cell proliferation, induce differentiation of regulatory T cells or support immune tolerance. Phenotypic characteristics of regulatory DCs (regDCs), as well as the mechanisms of T cell inhibition, vary in different experimental conditions and environments, suggesting high level of their plasticity and probably different origin. Although new data demonstrate that regDCs may play an important role at early stages of tumor development, functional differences and clinical significance of emergence of different myeloid regulatory cells (MDSCs, regDCs, M2 macrophages, N2 neutrophils, mast cells) in cancer remain to be determined.
    Cancer Microenvironment 06/2013; 6(2). DOI:10.1007/s12307-013-0133-3
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