scholarly journals miR-223-3p Inhibits Antigen Endocytosis and Presentation and Promotes the Tolerogenic Potential of Dendritic Cells through Targeting Mannose Receptor Signaling and Rhob

2020 ◽  
Vol 2020 ◽  
pp. 1-17 ◽  
Author(s):  
Hao-Cheng Tang ◽  
Yin-Yan Lai ◽  
Jing Zheng ◽  
Hong-Yan Jiang ◽  
Geng Xu
Keyword(s):  
Dendritic Cells ◽  
Cell Differentiation ◽  
Treg Cell ◽  
Mannose Receptor ◽  
Surface Expression ◽  
Inhibitory Effect ◽  
Mixed Lymphocyte Culture ◽  
Lymphocyte Culture ◽  
Antigen Uptake ◽  
Mhc Ii

Background. The role of miR-223-3p in dendritic cells (DCs) is unknown. This study is aimed at investigating the effect of miR-223-3p on the antigen uptake and presentation capacities of DCs and the underlying molecular mechanism. Methods. FITC-OVA antigen uptake and cell surface markers in bone marrow-derived DCs (BMDCs) were analyzed by flow cytometry. BMDCs were transfected with the miR-223-3p mimic or inhibitor. Cytokine levels were determined by ELISA. CD4+ T cell differentiation was determined by mixed lymphocyte culture assay. Results. OVA treatment significantly downregulated miR-223-3p in BMDCs. The miR-223-3p mimic significantly inhibited OVA-induced antigen uptake and surface expression of MHC-II on BMDCs (P<0.01). The miR-223-3p mimic increased TGF-β1 production in OVA-treated DCs (P<0.01). Mixed lymphocyte reaction showed that the miR-223-3p mimic significantly promoted Treg cell differentiation. In addition, the miR-223-3p mimic significantly upregulated CD103 in DCs, indicating the promotion of tolerogenic DCs. The miR-223-3p mimic downregulated Rhob protein in OVA-induced DCs. Rhob knockdown significantly suppressed the ability of FITC-OVA endocytosis (P<0.01) and surface MHC-II molecule expression (P<0.01) in BMDCs, promoting promoted Treg cell differentiation. Mannose receptor (MR) knockdown significantly upregulated miR-223-3p, downregulated Rhob protein in OVA-treated DCs, inhibited the FITC-OVA endocytosis and surface MHC-II expression in BMDCs, and promoted Treg cell differentiation (all P<0.01). Conclusion. These data suggest that miR-223-3p has an inhibitory effect on the antigen uptake and presentation capacities of BMDCs and promotes Treg cell differentiation, which is, at least partially, through targeting MR signaling and Rhob.

scholarly journals CD47 as a Potential Target to Therapy for Infectious Diseases

Antibodies ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 44
Author(s):  
Lamin B. Cham ◽  
Tom Adomati ◽  
Fanghui Li ◽  
Murtaza Ali ◽  
Karl S. Lang
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Infectious Diseases ◽  
Cancer Cells ◽  
Therapeutic Potential ◽  
Antiviral Effect ◽  
Surface Expression ◽  
Inhibitory Effect ◽  
Emerging Infections

The integrin associated protein (CD47) is a widely and moderately expressed glycoprotein in all healthy cells. Cancer cells are known to induce increased CD47 expression. Similar to cancer cells, all immune cells can upregulate their CD47 surface expression during infection. The CD47-SIRPa interaction induces an inhibitory effect on macrophages and dendritic cells (dendritic cells) while CD47-thrombospondin-signaling inhibits T cells. Therefore, the disruption of the CD47 interaction can mediate several biologic functions. Upon the blockade and knockout of CD47 reveals an immunosuppressive effect of CD47 during LCMV, influenza virus, HIV-1, mycobacterium tuberculosis, plasmodium and other bacterial pneumonia infections. In our recent study we shows that the blockade of CD47 using the anti-CD47 antibody increases the activation and effector function of macrophages, dendritic cells and T cells during viral infection. By enhancing both innate and adaptive immunity, CD47 blocking antibody promotes antiviral effect. Due to its broad mode of action, the immune-stimulatory effect derived from this antibody could be applicable in nonresolving and (re)emerging infections. The anti-CD47 antibody is currently under clinical trial for the treatment of cancer and could also have amenable therapeutic potential against infectious diseases. This review highlights the immunotherapeutic targeted role of CD47 in the infectious disease realm.

scholarly journals Trogocytosis of peptide–MHC class II complexes from dendritic cells confers antigen-presenting ability on basophils

2017 ◽  
Vol 114 (5) ◽  
pp. 1111-1116 ◽  
Author(s):  
Kensuke Miyake ◽  
Nozomu Shiozawa ◽  
Toshihisa Nagao ◽  
Soichiro Yoshikawa ◽  
Yoshinori Yamanishi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Cell Differentiation ◽  
Cell Surface ◽  
Mhc Class Ii ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Gm Csf ◽  
Mhc Ii ◽  
Th2 Cell ◽  
Antigen Presenting

Th2 immunity plays important roles in both protective and allergic responses. Nevertheless, the nature of antigen-presenting cells responsible for Th2 cell differentiation remains ill-defined compared with the nature of the cells responsible for Th1 and Th17 cell differentiation. Basophils have attracted attention as a producer of Th2-inducing cytokine IL-4, whereas their MHC class II (MHC-II) expression and function as antigen-presenting cells are matters of considerable controversy. Here we revisited the MHC-II expression on basophils and explored its functional relevance in Th2 cell differentiation. Basophils generated in vitro from bone marrow cells in culture with IL-3 plus GM-CSF displayed MHC-II on the cell surface, whereas those generated in culture with IL-3 alone did not. Of note, these MHC-II–expressing basophils showed little or no transcription of the corresponding MHC-II gene. The GM-CSF addition to culture expanded dendritic cells (DCs) other than basophils. Coculture of basophils and DCs revealed that basophils acquired peptide–MHC-II complexes from DCs via cell contact-dependent trogocytosis. The acquired complexes, together with CD86, enabled basophils to stimulate peptide-specific T cells, leading to their proliferation and IL-4 production, indicating that basophils can function as antigen-presenting cells for Th2 cell differentiation. Transfer of MHC-II from DCs to basophils was also detected in draining lymph nodes of mice with atopic dermatitis-like skin inflammation. Thus, the present study defined the mechanism by which basophils display MHC-II on the cell surface and appears to reconcile some discrepancies observed in previous studies.

scholarly journals POS0673 TOLEROGENIC DENDRITIC CELLS IN RHEUMATOID ARTHRITIS PATIENTS: NEWS AND PROMISES

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 581.2-581
Author(s):  
Y. Kurochkina ◽  
E. Chernykh ◽  
A. Sizikov
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Dendritic Cells ◽  
Mixed Lymphocyte Culture ◽  
Lymphocyte Culture ◽  
Moderate Activity ◽  
Blood Monocytes ◽  
Gm Csf ◽  
Hla Dr ◽  
Enhanced Expression

Background:Dendritic cells (DCs) are known to contribute to the pathogenesis of rheumatoid arthritis (RA) through presentation of cartilage glycoprotein, production of proinflammatory cytokines and activation of Th1/Th17 responses. Along with stimulating activity, DCs may exhibit suppressive functions via capacity to induce T cell apoptosis/anergy and to generate regulatory T cells. Since these DCs have potential to control autoreactive T-lymphocytes, the enhancing of tolerogenic properties of DCs seems to be a new important strategy in treatment of RA. Dexamethasone is widely used in clinical practice and can be used as a tolerogenic substance. Therefore, the properties of DCs generated in presence of dexamethasone are of great clinical interests.Objectives:The aim of our study is to describe the properties of tolerogenic DCs, generated with dexamethasone in patients with RA and their influence on autologous T-cells.Methods:Sixty five patients with RA with high and moderate activity of disease were recruited in this study. All patients follow ACR/EULAR criteria (2010). All studies were performed after receiving informed consent. All patients received conventional synthetic DMARDs. DCs were generated from blood monocytes culturing for 5 days with GM-CSF and IFN-α in the presence dexamethasone (dexDCS), applied on third day. LPS as maturation stimuli was added on fourth day. The expression of CD14, CD83, HLA-DR, TLR-2 on the surface of DCs was measured by flow cytometry. The functions of DCs were evaluated by measuring cytokine production and DCs allostimulatory activity in mixed lymphocyte culture. Mature DCs generated in absence of dexamethasone used as control.Results:We revealed that dexDCs are characterized by enhanced expression of CD14+cells and decreased number of CD83+cells but percent of HLA-DR+cells were constant (about 85). DexDCs show high expression of TLR-2 is seen as tolerogenic molecule (75%vs51%, p=0.05 compared to control). DexDCs also have marked prominent increase of TNFα/IL-10 ratio in contrast to control (0.59 vs 1.8, p=0.03). DexDCs suppressed proliferation of allogenic T-cells (2005 vs 7980 cpm, p=0.0002). To assess the stability of the DC in the proinfflamatory micro-environment after assessing stimulatory activity dexDCs were then cultivated with LPS and allostimulatory activity were evaluated one more. The stimulation activity dexDCs after incubation with LPS were not increase (4692 vs 6053 cpm, p=0.7). Also earlier we showed possibility of dexDCs induse apoptosis of autologous T-cells, activation of CD4+IL10+Tr1 and possession of antigen-specific suppression.Conclusion:The data obtained indicate that dexDCs from RA patients have the main tolerogenic features and stable in inflammatory environment that proves their potential in the treatment of rheumatoid arthritis.Disclosure of Interests:None declared

Rapamycin inhibits macropinocytosis and mannose receptor–mediated endocytosis by bone marrow–derived dendritic cells

Blood ◽  
2002 ◽  
Vol 100 (3) ◽  
pp. 1084-1087 ◽  
Author(s):  
Holger Hackstein ◽  
Timucin Taner ◽  
Alison J. Logar ◽  
Angus W. Thomson
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Dendritic Cells ◽  
Apoptotic Cell ◽  
Mannose Receptor ◽  
Antigen Uptake ◽  
Color Flow ◽  
Murine Bone Marrow ◽  
Receptor Mediated Endocytosis

Abstract Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that use 2 major pathways for antigen uptake: constitutive macropinocytosis and mannose receptor–mediated endocytosis. Efficient endocytosis is critical for DCs to fulfill their sentinel function in immunity. We investigated the influence of the immunosuppressive macrolide rapamycin on macropinocytosis of fluorescein isothiocyanate (FITC)–albumin and mannose receptor–mediated endocytosis of FITC-dextran by murine bone marrow–derived DCs by flow cytometry. The data show that (1) at a low, physiologically relevant concentration (1 ng/mL), rapamycin impairs macropinocytosis and mannose receptor–mediated endocytosis; (2) the effects are independent of DC maturation and can be demonstrated specifically in immature CD11c+ major histocompatibility complex (MHC) class IIlo DCs by 3-color flow cytometry; (3) inhibition of endocytosis is not related to apoptotic cell death; and (4) molar excess of the structurally related molecule FK506 inhibits the actions of rapamycin. The inhibitory effects of rapamycin on DC endocytosis were confirmed in vivo. To our knowledge, this is the first report that a clinically relevant immunosuppressant inhibits DC endocytosis.

scholarly journals Angiotensin II Regulates Dendritic Cells through Activation of NF-κB /p65, ERK1/2 and STAT1 Pathways

2017 ◽  
Vol 42 (4) ◽  
pp. 1550-1558 ◽  
Author(s):  
Yan Meng ◽  
Chen Chen ◽  
Yang Liu ◽  
Cui Tian ◽  
Hui-Hua Li
Keyword(s):  
Dendritic Cells ◽  
Angiotensin Ii ◽  
Mixed Lymphocyte Culture ◽  
Lymphocyte Culture ◽  
Ang Ii ◽  
Stat1 Signaling ◽  
Underlying Mechanisms ◽  
And Migration ◽  
Dc Maturation

Background: Activation of dendritic cells (DCs) is necessary to initiate immune responses. Angiotensin II (Ang II) has been reported to have a proinflammatory and immunomodulatory function. However, the role of Ang II in regulation of DCs and the underlying mechanisms remain illdefined. Methods: The effects of Ang II on the proliferation, maturation, phagocytosis, migration, and communication with T cells of DCs were analysed utilizing MTT, flow cytometry, ELISA, transwell assay and mixed lymphocyte culture. Results: We found that Ang II treatment significantly inhibited proliferation and phagocytic activity of DCs, but promoted the DC maturation and migration well as the expression of pro-inflammatory cytokines by DCs. In addition, Ang II also stimulated DC-mediated T cell proliferation. These effects were associated with activation of p65/NF-κB, ERK1/2 and STAT1 signaling pathways in DCs. Conclusions: Our results demonstrate that Ang II activates DCs partially through p65/NF-κB, ERK1/2 and STAT1 pathways, and suggest a potential therapeutic target of DC-mediated inflammatory disorders.

scholarly journals The tumor suppressor p15Ink4b regulates the differentiation and maturation of conventional dendritic cells

Blood ◽  
2012 ◽  
Vol 119 (21) ◽  
pp. 5005-5015 ◽  
Author(s):  
Joanna Fares ◽  
Richard Koller ◽  
Rita Humeniuk ◽  
Linda Wolff ◽  
Juraj Bies
Keyword(s):  
Dendritic Cells ◽  
Tumor Suppressor ◽  
Immune Responses ◽  
Ex Vivo ◽  
Positive Role ◽  
Antigen Uptake ◽  
Mhc Ii ◽  
T Cell Stimulation ◽  
Elevated Activity ◽  
Antigen Presenting

Abstract The tumor suppressor p15Ink4b is frequently inactivated by methylation in acute myeloid leukemia and premalignant myeloid disorders. Dendritic cells (DCs) as potent APCs play critical regulatory roles in antileukemic immune responses. In the present study, we investigated whether p15Ink4b can function as modulator of DC development. The expression of p15Ink4b is induced strongly during differentiation and activation of DCs, and its loss resulted in significant quantitative and qualitative impairments of conventional DC (cDC) development. Accordingly, ex vivo–generated BM-derived DCs from p15Ink4b-knockout mice express significantly decreased levels of the antigen-presenting (MHC II) and costimulatory (CD80 and CD86) molecules and have impaired immunostimulatory functions, such as antigen uptake and T-cell stimulation. Reexpression of p15Ink4b in progenitors restored these defects, and confirmed a positive role for p15Ink4b during cDC differentiation and maturation. Furthermore, we have shown herein that p15Ink4b expression increases phosphorylation of Erk1/Erk2 kinases, which leads to an elevated activity of the PU.1 transcription factor. In conclusion, our results establish p15Ink4b as an important modulator of cDC development and implicate a novel function for this tumor suppressor in the regulation of adaptive immune responses.

scholarly journals Cytotoxic Activity of Dendritic Cells as a Possible Mechanism of Negative Regulation of T Lymphocytes in Pulmonary Tuberculosis

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Ludmila V. Sakhno ◽  
Marina A. Tikhonova ◽  
Tamara V. Tyrinova ◽  
Olga Yu. Leplina ◽  
Ekaterina Ya. Shevela ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Pulmonary Tuberculosis ◽  
Cell Apoptosis ◽  
Mixed Lymphocyte Culture ◽  
Lymphocyte Culture ◽  
Blood Monocytes ◽  
General Group ◽  
T Cell Apoptosis

The PD-1/B7-H1-mediated induction of T cell apoptosis/anergy as a possible mechanism of immune response failure was studied in 76 patients with pulmonary tuberculosis (TB) with normal and low-proliferative response to antigens ofM. tuberculosis(purified protein derivative (PPD)). It was revealed that dendritic cells (DCs), generatedin vitrofrom patient blood monocytes with GM-CSF + IFN-α, were characterized by increased B7-H1 expression, upproduction of IL-10, and reducing of allostimulatory activity in mixed lymphocyte culture (MLC). Moreover, DCs of patients with TB were able to enhance T cell apoptosis and to block T-cell division in MLC. It was shown that neutralizing anti-PD1 antibodies significantly decreased the proapoptogenic/tolerogenic effect of DCs. Correlation analysis revealed a direct relationship between IL-10 production and level of B7-H1 expression in the general group of investigated patients. It was demonstrated that generation of healthy donor DCs in the presence of IL-10 led to an increase in the number of DCs-expressed B7-H1 molecule, DC proapoptogenic activity, and a decrease in their allostimulatory activity. Obviously, the revealed phenomenon of the PD-1/B7-H1-mediated pro-apoptogenic activity of DCs is clinically significant since the cytotoxic/tolerogenic potential of DCs is more pronounced in patients with PPD anergy.

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