Figure - available from: Frontiers in Immunology
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Decoy receptor 3 (DcR3) suppresses FasL/TRAIL-related T-cell activation and proliferation, promotes effector T-cell (Teff) necrosis and apoptosis, and inhibits pro-inflammatory cytokines. (A, B) Teffs are obtained from naïve female T-cells from LN cells or spleen and are activated by male bone marrow-derived dendritic cells + lipopolysaccharide. IgG1, DcR3.Fc, FasL/TRAIL + IgG1, and FasL/TRAIL + DcR3.Fc-treated wild-type (WT) T-cells for 24 h were subcategorized into CD4CD69 and CD4CD44 and further presented by histogram and percentage of the indicated immune cells. The cells were double-stained with anti-mCD4-allophycocyanin (APC)-cyanine7(cy7)/CD44-APC or CD69-APC. Control means without treatment, not even IgG1 alone. (C) Carboxyfluorescein diacetate, succinimidyl ester (CFSE) labeling assay. CFSE-labeled T-cells were treated with IgG1, DcR3.Fc, FasL/TRAIL + IgG1, or FasL/TRAIL + DcR3.Fc for 36 h before the flow cytometry analysis. Control means without treatment, not even IgG1 alone. (D, E) Regulatory T-cells were triple-stained with anti-mCD4-APC-cy7/CD25-FITC/Foxp3-Alexa Fluor and subjected to flow cytometry; the percentage of positively stained cells is indicated in each quadrant plot. Control means without treatment, not even IgG1 alone. (F) Necrotic and apoptotic cells were evaluated by Annexin-V-FITC/PI staining. Left panel, CD4; right panel, CD4. (G) Detection of surface FasR in the indicated Teffs. (H) Dose-dependent effect of DcR3.Fc on FasR expression in the indicated Teffs. The cells were incubated with 100 ng/ml FasL, 100 ng/ml TRAIL, and 0, 2.5, 5, and 10 μg/ml DcR3.Fc, and then the FasR mRNA levels were determined using real-time PCR. (I) Tumor necrosis factor (TNF)-α secretion suppression. The supernatants were harvested 36 h after T-cell priming to test TNF-α using ELISA. (J) Interferon (IFN)-γ inhibition in DcR3.Fc-treated Teffs was evaluated using real-time PCR. (K) IFN-γ of culture medium in time sequence (solid lines, CD4 T-cells; dashed lines, CD8 T-cells). (A–K) All experiment systems are in vitro systems of acute cell rejection model for 36 h. One set of representative data from at least four experiments (n=4) is shown. The Kruskal–Wallis test, followed by Bonferroni post-hoc analysis, was used for multiple testing (H–J). For two independent groups (A–C, E, F), a nonparametric test, Mann–Whitney U-test, was used. The data are presented as mean ± SE. F, FasL; I, human IgG1; D, DcR3.Fc; T, TRAIL; D0, 0 μg/ml DcR3.Fc; D2.5, 2.5 μg/ml DcR3.Fc; D5, 5 μg/ml DcR3.Fc; D10, 10 μg/ml DcR3.Fc; F0, 0 ng/ml FasL; F100, 100 ng/ml FasL; T100, 100 ng/ml TRAIL.
Source publication
Background
Decoy receptor 3 (DcR3) belongs to the tumor necrosis factor (TNF) receptor superfamily and neutralizes TNF ligands, including FasL and TRAIL, to prevent T activation during T-cell priming. However, the cellular mechanisms underlying acute cell-mediated rejection (ACMR) remain unknown.
Methods
We generated DcR3 transgenic (Tg) mice and...
Citations
... Blockade of TRAIL-DR3 interaction prevents acute rejection in mouse kidney transplantation [161]. BTLA HVEM Inhibiting DCs maturation [94], proinflammatory cytokines production in DCs [162]. ...
Gene editing of living cells has become a crucial tool in medical research, enabling scientists to address fundamental biological questions and develop novel strategies for disease treatment. This technology has particularly revolutionized adoptive transfer cell therapy products, leading to significant advancements in tumor treatment and offering promising outcomes in managing transplant rejection, autoimmune disorders, and inflammatory diseases. While recent clinical trials have demonstrated the safety of tolerogenic dendritic cell (TolDC) immunotherapy, concerns remain regarding its effectiveness. This review aims to discuss the application of gene editing techniques to enhance the tolerance function of dendritic cells (DCs), with a particular focus on preclinical strategies that are currently being investigated to optimize the tolerogenic phenotype and function of DCs. We explore potential approaches for in vitro generation of TolDCs and provide an overview of emerging strategies for modifying DCs. Additionally, we highlight the primary challenges hindering the clinical adoption of TolDC therapeutics and propose future research directions in this field.
... Besides exercising a decoy function, DcR3 can also perform a non-decoy function, i.e., DcR3 acts as an effector molecule that directly regulates the activity of many cell types [41]. Soluble DcR3-Fc binds to CD14+ monocytes and regulates their differentiation and maturation into DCs; CD4+ T cells co-cultured with DcR3-Fc-treated DCs proliferate in the Th2 phenotype; DcR3 drives the conversion of macrophages to the M2 phenotype; and DcR3 both induces actin reorganization and increases cell adhesion in human monocytes [28,[42][43][44][45][46]. ...
Decoy receptor 3 (DcR3), a soluble glycosylated protein in the tumor necrosis factor receptor superfamily, plays a role in tumor and inflammatory diseases. Sepsis is a life-threatening organ dysfunction caused by the dysregulation of the response to infection. Currently, no specific drug that can alleviate or even cure sepsis in a comprehensive and multi-level manner has been found. DcR3 is closely related to sepsis and considerably upregulated in the serum of those patients, and its upregulation is positively correlated with the severity of sepsis and can be a potential biomarker for diagnosis. DcR3 alone or in combination with other markers has shown promising results in the early diagnosis of sepsis. Furthermore, DcR3 is a multipotent immunomodulator that can bind FasL, LIGHT, and TL1A through decoy action, and block downstream apoptosis and inflammatory signaling. It also regulates T-cell and macrophage differentiation and modulates immune status through non-decoy action; therefore, DcR3 could be a potential drug for the treatment of sepsis. The application of DcR3 in the treatment of a mouse model of sepsis also achieved good efficacy. Here, we introduce and discuss the progress in, and suggest novel ideas for, research regarding DcR3 in the diagnosis and treatment of sepsis.
Background: Over the years, the morbidity and mortality due to cancer have continued to increase worldwide. Plants are well utilized in Nigeria ethno-medicine for cancer treatment. However, scientific evidence, particularly at the molecular level, has been lacking, and biodiversity loss is a threat. Aim of the study: The cytotoxic activity of the leaves of six plants used in Nigeria ethno-medicine was investigated and the molecular pathway of cytotoxic action of two active extracts on four cancer cell lines (A549, RD, MCF-7, and HeLa) was also assessed. Materials and methods: Cytotoxic activities of the plant extracts were assessed on breast (MCF-7), lung (A549), cervical (HeLa), adenocarcinoma and rhabdomyosarcoma (RD) cells using MTT cell viability assay in a time-dependent manner. The sandwich ELISA method was used to assess the protein expressions (Bcl-2, BAX, and executioner caspase 3) involved in the apoptotic pathway in cancer cells after treatment with cytotoxic extracts. UHPLC-MS/MS approach was used to analyze the possible bioactive phytochemicals of the cytotoxic plant extract. Results: Uvaria chamae and Dicliptera paniculata extracts displayed good cytotoxicity across all cell lines in a time- and concentration-dependent manner (CC50
Binding of CD95, a cell surface death receptor, to its homologous ligand CD95L, transduces a cascade of downstream signals leading to apoptosis crucial for immune homeostasis and immune surveillance. Although CD95 and CD95L binding classically induces programmed cell death, most tumor cells show resistance to CD95L-induced apoptosis. In some cancers, such as glioblastoma, CD95-CD95L binding can exhibit paradoxical functions that promote tumor growth by inducing inflammation, regulating immune cell homeostasis, and/or promoting cell survival, proliferation, migration, and maintenance of the stemness of cancer cells. In this review, potential mechanisms such as the expression of apoptotic inhibitor proteins, decreased activity of downstream elements, production of nonapoptotic soluble CD95L, and non-apoptotic signals that replace apoptotic signals in cancer cells are summarized. CD95L is also expressed by other types of cells, such as endothelial cells, polymorphonuclear myeloid-derived suppressor cells, cancer-associated fibroblasts, and tumor-associated microglia, and macrophages, which are educated by the tumor microenvironment and can induce apoptosis of tumor-infiltrating lymphocytes, which recognize and kill cancer cells. The dual role of the CD95-CD95L system makes targeted therapy strategies against CD95 or CD95L in glioblastoma difficult and controversial. In this review, we also discuss the current status and perspective of clinical trials on glioblastoma based on the CD95-CD95L signaling pathway.
