Naturally occurring CD1c+ human regulatory dendritic cells: immunoregulators that are expanded in response to E. coli infection.
ABSTRACT 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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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;
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ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. HCC-induced immunosuppression often leads to ineffectiveness of immuno-promoting therapies. Now suppressing the suppressors has become the potential strategy for cancer immunotherapy. So, figuring out the immunosuppressive mechanisms induced and employed by HCC will be helpful to the design and application of HCC immunotherapy. Here we identified one new subset of human CD14(+) CTLA-4(+) regulatory dendritic cells (CD14(+) DCs) in HCC patients, representing ~13% of PBMCs. CD14(+) DCs significantly suppress T cell response in vitro via IL-10 and IDO. Unexpectedly, CD14(+) DCs expressed high levels of CTLA-4 and PD-1, and CTLA-4 was found to be essential to IL-10 and IDO production. So, we identified a novel human tumor-induced regulatory DC subset, which suppresses anti-tumor immune response via CTLA-4-dependent IL-10 and IDO production, thus indicating the important role of non-regulatory T cell-derived CTLA-4 in tumor immune escape or immunosuppression. Our data outline one mechanism for HCC to induce systemic immunosuppression by expanding CD14(+) DCs which may contribute to HCC progression. Thus, our results add new insight to the mechanism for HCC-induced immunosuppression and may also provide a previously unrecognized target of immunotherapy for HCC. (Hepatology 2013;).Hepatology 08/2013; · 12.00 Impact Factor
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ABSTRACT: Dendritic cells (DCs) are critical to initiate the immune response and maintain tolerance, depending on different status and subsets. The expression profiles of microRNAs (miRNAs) in various DC subsets and haematopoietic stem cells (HSCs), which generate DCs, remain to be fully identified. Here we examine miRNomes of mouse bone marrow HSCs, immature DCs, mature DCs and IL-10/NO-producing regulatory DCs by deep sequencing. We identify numerous stage-specific miRNAs and histone modification in HSCs and DCs at different differentiation stages. miR-30b, significantly upregulated via a TGF-beta/Smad3-mediated epigenetic pathway in regulatory DCs, can target Notch1 to promote IL-10 and NO production, suggesting that miR-30b is a negative regulator of immune response. We also identify miRNomes of in vivo counterparts of mature DCs and regulatory DCs and systematically compare them with DCs cultured in vitro. These results provide a resource for studying roles of miRNAs in stem cell biology, development and functional regulation of DC subsets.Nature Communications 12/2013; 4:2903. · 10.02 Impact Factor