Interferon-α and interleukin-12 are induced, respectively, by double-stranded DNA and single-stranded RNA in human myeloid dendritic cells

Bone marrow-derived dendritic cells (DC) represent a family of antigen-presenting cells (APC) with varying phenotypes. For example, in mice, CD8α+ and CD8α− DC are thought to represent cells of lymphoid and myeloid origin, respectively. Langerhans cells (LC) of the epidermis are typical myeloid DC; they do not express CD8α, but they do express high levels of myeloid antigens such as CD11b and FcγR. By contrast, thymic DC, which derive from a lymphoid-related progenitor, express CD8α but only low levels of myeloid antigens. CD8α+ DC are also found in the spleen and lymph nodes (LN), but the origin of these cells has not been determined. By activating and labeling CD8α− epidermal LC in vivo, it was found that these cells expressed CD8α on migration to the draining LN. Similarly, CD8α− LC generated in vitro from a CD8 wild-type mouse and injected into the skin of a CD8αKO mouse expressed CD8α when they reached the draining LN. The results also show that CD8α+ LC are potent APC. After migration from skin, they localized in the T-cell areas of LN, secreted high levels of interleukin-12, interferon-γ, and chemokine-attracting T cells, and they induced antigen-specific T-cell activation. These results demonstrate that myeloid DC in the periphery can express CD8α when they migrate to the draining LN. CD8α expression on these DC appears to reflect a state of activation, mobilization, or both, rather than lineage.

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Plasmacytoid dendritic cells accumulate in spleens from chronically HIV-infected patients but barely participate in interferon-α expression

Blood ◽

10.1182/blood-2008-07-170803 ◽

2009 ◽

Vol 113 (24) ◽

pp. 6112-6119 ◽

Cited By ~ 61

Author(s):

Michelina Nascimbeni ◽

Leïla Perié ◽

Laurent Chorro ◽

Seckou Diocou ◽

Louis Kreitmann ◽

...

Keyword(s):

Dendritic Cells ◽

Marginal Zone ◽

Plasmacytoid Dendritic Cells ◽

Interferon Α ◽

Functional Assay ◽

Myeloid Dendritic Cells ◽

Hiv Patients ◽

Human Spleen ◽

Red Pulp

AbstractWe characterized the localization, phenotype, and some functions of plasmacytoid dendritic cells (pDCs) in the human spleen. pDCs were localized in the marginal zone and the periarteriolar region. Some were also found in the red pulp. pDCs were immature by phenotypic labeling, consistently with their capacity to internalize Dextran in a functional assay. In spleens from HIV-infected patients with thrombocytopenic purpura, these characteristics were unaffected. However, an accumulation of pDCs, but not myeloid dendritic cells (mDCs), was observed in some HIV+ patients, correlating with high proviral loads. Moreover, although undetectable in most HIV− patients, interferon-α (IFN-α) production was evidenced in situ and by flow cytometry in most HIV+ patients. IFN-α was located in the marginal zone. Surprisingly, IFN-α colocalized only with few pDCs, but rather with other cells, including T and B lymphocytes, mDCs, and macrophages. Therefore, pDCs accumulated in spleens from HIV+ patients with high proviral loads, but they did not seem to be the main IFN-α producers.

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Immunomodulatory drugs suppress Th1-inducing ability of dendritic cells but enhance Th2-mediated allergic responses

Blood Advances ◽

10.1182/bloodadvances.2019001410 ◽

2020 ◽

Vol 4 (15) ◽

pp. 3572-3585

Author(s):

Vien Phan ◽

Tomoki Ito ◽

Muneo Inaba ◽

Yoshiko Azuma ◽

Kayoko Kibata ◽

...

Keyword(s):

Dendritic Cells ◽

Interleukin 12 ◽

Immunomodulatory Drugs ◽

Myeloid Dendritic Cells ◽

Th2 Response ◽

Cell Responses ◽

Th2 Cell ◽

Ox40 Ligand ◽

Ligand Expression ◽

Good Partial Response

Abstract Immunomodulatory drugs (IMiDs), lenalidomide and pomalidomide, are widely used treatments for multiple myeloma; however, they occasionally lead to episodes of itchy skin and rashes. Here, we analyzed the effects of IMiDs on human myeloid dendritic cells (mDCs) as major regulators of Th1 or Th2 responses and the role they play in allergy. We found that lenalidomide and pomalidomide used at clinical concentrations did not affect the survival or CD86 and OX40-ligand expression of blood mDCs in response to lipopolysaccharide (LPS) and thymic stromal lymphopoietin (TSLP) stimulation. Both lenalidomide and pomalidomide dose-dependently inhibited interleukin-12 (IL-12) and TNF production and STAT4 expression, and enhanced IL-10 production in response to LPS. When stimulated with TSLP, both IMiDs significantly enhanced CCL17 production and STAT6 and IRF4 expression and promoted memory Th2-cell responses. In 46 myeloma patients, serum CCL17 levels at the onset of lenalidomide-associated rash were significantly higher than those without rashes during lenalidomide treatment and those before treatment. Furthermore, serum CCL17 levels in patients who achieved a very good partial response (VGPR) were significantly higher compared with a less than VGPR during lenalidomide treatment. The median time to next treatment was significantly longer in lenalidomide-treated patients with rashes than those without. Collectively, IMiDs suppressed the Th1-inducing capacity of DCs, instead promoting a Th2 response. Thus, the lenalidomide-associated rashes might be a result of an allergic response driven by Th2-axis activation. Our findings suggest clinical efficacy and rashes as a side effect of IMiDs are inextricably linked through immunostimulation.

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Dendritic Cell Activation by Recombinant Hemagglutinin Proteins of H1N1 and H5N1 Influenza A Viruses

Journal of Virology ◽

10.1128/jvi.01316-10 ◽

2010 ◽

Vol 84 (22) ◽

pp. 12011-12017 ◽

Cited By ~ 24

Author(s):

Wen-Chun Liu ◽

Shih-Chang Lin ◽

Yen-Ling Yu ◽

Ching-Liang Chu ◽

Suh-Chin Wu

Keyword(s):

Dendritic Cells ◽

Influenza A ◽

Cell Activation ◽

Influenza Virus Infection ◽

Proteinase K ◽

Interleukin 12 ◽

Dendritic Cell Activation ◽

Myeloid Dendritic Cells ◽

H5n1 Influenza ◽

Recombinant Hemagglutinin

ABSTRACT Since dendritic cells may play a key role in defense against influenza virus infection, we examined the effects of recombinant hemagglutinin (HA) proteins derived from mouse-adapted H1N1 (A/WSN/1933), swine-origin 2009 pandemic H1N1 (A/Texas/05/2009), and highly pathogenic avian influenza H5N1 (A/Thailand/KAN-1/2004) viruses on mouse myeloid dendritic cells (mDCs). The results reveal that tumor necrosis factor alpha (TNF-α), interleukin-12 (IL-12) p70, and major histocompatibility complex class II (MHC-II) expression was increased in mDCs after treatment with recombinant HA proteins of H1N1 and H5N1. The specificity of recombinant HA treatments for mDC activation was diminished after proteinase K digestion. HA apparently promotes mDC maturation by enhancing CD40 and CD86 expression and suppressing endocytosis. No significant differences in mDC activation were observed among recombinant proteins of H1N1 and H5N1. The stimulation of mDCs by HA proteins of H1N1 and H5N1 was completely MyD88 dependent. These findings may provide useful information for the development of more-effective influenza vaccines.

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Role of the P2Y6 receptor of UDP in the modulation of murine dendritic cell functions and Th1 polarisation of the immune response

JOURNAL OF MEDICINES DEVELOPMENT SCIENCES ◽

10.18063/jmds.2016.01.002 ◽

2016 ◽

Vol 2 (1) ◽

pp. 30

Author(s):

Dorothée Cammarata ◽

Abduelhakem Ben Addi ◽

Eva D’Amico ◽

Bernard Robaye

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Interleukin 12 ◽

Uridine Diphosphate ◽

Myeloid Dendritic Cells ◽

Cell Functions ◽

P2y6 Receptor ◽

Deficient Mice

Numerous studies have demonstrated the role of uridine diphosphate (UDP) and its P2Y6 receptor in the inflammatory reaction and innate immunity. However, the importance of the P2Y6 receptor in the adaptive immune response remains unclear. In this study, we demonstrate that the P2Y6 receptor is functionally expressed in murine bone marrow dendritic cells (BMDC). UDP induced a Ca2+ transient in these cells that was decreased in P2Y6-deficient mice. UDP also increased the endocytosis of fluorescein isothiocyanate-dextran (FITC-dextran) and amplified the secretion of interleukin 12-p70 (IL-12p70) induced by CpG; these responses were abolished in P2Y6-deficient mice. In vivo experiments showed that the serum level of specific IgG2c after immunisation with ovalbumin was decreased in P2Y6-deficient mice, while the level of specific IgG1 was unchanged. These data suggest that the P2Y6-mediated effects of UDP on myeloid dendritic cells play a role in the in vivo Th1 skewing of the immune response.

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Quantitative and Functional Differences between Peripheral Blood Myeloid Dendritic Cells from Patients with Pleural and Parenchymal Lung Tuberculosis

Clinical and Vaccine Immunology ◽

10.1128/cvi.00132-06 ◽

2006 ◽

Vol 13 (12) ◽

pp. 1299-1306 ◽

Cited By ~ 11

Author(s):

Marc Mendelson ◽

Willem A. Hanekom ◽

Siyabulela Ntutela ◽

Monica Vogt ◽

Lafras Steyn ◽

...

Keyword(s):

Dendritic Cells ◽

Whole Blood ◽

Peripheral Blood ◽

Interleukin 12 ◽

Myeloid Dendritic Cells ◽

Whole Blood Assay ◽

Lung Tuberculosis ◽

Plasmacytoid Dcs ◽

Parenchymal Disease ◽

Circulating Levels

ABSTRACT Dendritic cells (DCs) play a pivotal role in generating protective host immunity to Mycobacterium tuberculosis. Few studies have addressed DC function in the context of active tuberculosis (TB), largely due to technical constraints in obtaining adequate numbers of DC from sick patients. We quantitated peripheral blood myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in the whole blood of patients with active TB and show that blood from patients with pleural TB was characterized by high circulating levels of mDCs. We also developed and optimized a novel whole-blood assay to study mDC production of the Th1-promoting cytokine interleukin 12 (IL-12) and upregulation of the maturation marker CCR7 after incubation with mycobacteria. We found that pleural TB was associated with increased IL-12 production and CCR7 expression compared to lung parenchymal disease. Our findings suggest important differences in innate immunity between patients with different forms of active TB, and this may contribute to the differences in natural history observed between the two groups.

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Differentiation of myeloid dendritic cells into CD8α-positive dendritic cells in vivo

Blood ◽

10.1182/blood.v96.5.1865 ◽

2000 ◽

Vol 96 (5) ◽

pp. 1865-1872 ◽

Cited By ~ 78

Author(s):

Miriam Merad ◽

Lawrence Fong ◽

Jakob Bogenberger ◽

Edgar G. Engleman

Keyword(s):

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Wild Type Mouse ◽

Interleukin 12 ◽

Myeloid Dendritic Cells ◽

Myeloid Antigens

Abstract Bone marrow-derived dendritic cells (DC) represent a family of antigen-presenting cells (APC) with varying phenotypes. For example, in mice, CD8α+ and CD8α− DC are thought to represent cells of lymphoid and myeloid origin, respectively. Langerhans cells (LC) of the epidermis are typical myeloid DC; they do not express CD8α, but they do express high levels of myeloid antigens such as CD11b and FcγR. By contrast, thymic DC, which derive from a lymphoid-related progenitor, express CD8α but only low levels of myeloid antigens. CD8α+ DC are also found in the spleen and lymph nodes (LN), but the origin of these cells has not been determined. By activating and labeling CD8α− epidermal LC in vivo, it was found that these cells expressed CD8α on migration to the draining LN. Similarly, CD8α− LC generated in vitro from a CD8 wild-type mouse and injected into the skin of a CD8αKO mouse expressed CD8α when they reached the draining LN. The results also show that CD8α+ LC are potent APC. After migration from skin, they localized in the T-cell areas of LN, secreted high levels of interleukin-12, interferon-γ, and chemokine-attracting T cells, and they induced antigen-specific T-cell activation. These results demonstrate that myeloid DC in the periphery can express CD8α when they migrate to the draining LN. CD8α expression on these DC appears to reflect a state of activation, mobilization, or both, rather than lineage.

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