Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Nonagonistic Dectin-1 ligand transforms CpG into a multitask nanoparticulate TLR9 agonist.

ABSTRACT: CpG DNA, a ligand for Toll-like receptor 9 (TLR9), has been one of the most promising immunotherapeutic agents. Although there are several types of potent humanized CpG oligodeoxynucleotide (ODN), developing "all-in-one" CpG ODNs activating both B cells and plasmacytoid dendritic cells forming a stable nanoparticle without aggregation has not been successful. In this study, we generated a novel nanoparticulate K CpG ODN (K3) wrapped by the nonagonistic Dectin-1 ligand schizophyllan (SPG), K3-SPG. In sharp contrast to K3 alone, K3-SPG stimulates human peripheral blood mononuclear cells to produce a large amount of both type I and type II IFN, targeting the same endosome where IFN-inducing D CpG ODN resides without losing its K-type activity. K3-SPG thus became a potent adjuvant for induction of both humoral and cellular immune responses, particularly CTL induction, to coadministered protein antigens without conjugation. Such potent adjuvant activity of K3-SPG is attributed to its nature of being a nanoparticle rather than targeting Dectin-1 by SPG, accumulating and activating antigen-bearing macrophages and dendritic cells in the draining lymph node. K3-SPG acting as an influenza vaccine adjuvant was demonstrated in vivo in both murine and nonhuman primate models. Taken together, K3-SPG may be useful for immunotherapeutic applications that require type I and type II IFN as well as CTL induction.

SUBMITTER: Kobiyama K

PROVIDER: S-EPMC3939924 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

pDC Activation by TLR7/8 Ligand CL097 Compared to TLR7 Ligand IMQ or TLR9 Ligand CpG.

Project description:Plasmacytoid dendritic cells (pDCs) express high levels of the toll-like receptors (TLRs) TLR7 and TLR9. In response to TLR7 and TLR9 ligands, pDCs are primary producers of type I interferons. Our previous study demonstrated that pDCs activated by the TLR7 ligand imiquimod (IMQ) and the TLR9 ligand CpG A can kill breast cancer cells in vitro and inhibit tumor growth in vivo. Moreover, we observed a distinctive morphological, phenotypic change in pDCs after activation by IMQ and CpG A. However, the effect of other TLR7 and TLR9 ligands on pDCs remains less understood. In this study, we treat pDCs with the TLR7 ligand IMQ, TLR7/8 ligands (CL097 and CL075), and three TLR9 ligands (different types of CpGs). The size of pDCs increased significantly after activation by TLR7, or TLR7/8 ligands. TLR7, TLR7/8, and TLR9 ligands similarly modulated cytokine release, as well as protein expression of pDC markers, costimulatory molecules, and cytotoxic molecules. Interestingly, TLR7/8 ligands, especially CL097, induced stronger responses. These results are relevant to the further study of the role and mechanism of pDC-induced antitumor effects and may aid in the development of a new strategy for future tumor immunotherapy.

| S-EPMC6481147 | biostudies-literature

Stimulation of isolated plasmacytoid dendritic cells (pDCs) with TLR9 agonist CpG C (CpG) and TLR7 agonist imiquimod (IMQ)

Project description:The purpose of this experiment was to assess the genes upregulated when pDCs were stimulated with TLR7 agonist imiquimod and TLR9 agonist CpG C.

2016-03-17 | GSE79272 | GEO

Stimulation of isolated plasmacytoid dendritic cells (pDCs) with TLR9 agonist CpG C (CpG) and TLR7 agonist imiquimod (IMQ)

Project description:The purpose of this experiment was to assess the genes upregulated when pDCs were stimulated with TLR7 agonist imiquimod and TLR9 agonist CpG C. pDCs were isolated from six healthy donors by FACS sorting, and were stimulated with CpG and imiquimod for 18 hours, after which RNA was extracted for next generation sequencing on the Illumina HiSeq platform. Unstimulated samples were included as controls.

2016-03-17 | E-GEOD-79272 | biostudies-arrayexpress

TLR9 ligand CpG-ODN applied to the injured mouse cornea elicits retinal inflammation.

Project description:During bacterial and viral infections, unmethylated CpG-DNA released by proliferating and dying microbes is recognized by toll-like receptor (TLR) 9 in host cells, initiating innate immune responses. Many corneal infections occur secondary to epithelial breaches and represent a major cause of vision impairment and blindness globally. To mimic this clinical situation, we investigated mechanisms of TLR9 ligand-induced corneal inflammation in mice after epithelial debridement. Application of CpG oligodeoxynucleotides (ODNs) resulted in neutrophil and macrophage infiltration to the cornea and loss of transparency. By 6 hours after CpG-ODN administration, TLR9 mRNA was increased in the cornea and retina. In vivo clinical examination at 24 hours revealed inflammatory infiltrates in the vitreous and retina, which were confirmed ex vivo to be neutrophils and macrophages, along with activated resident microglia. CpG-ODN-induced intraocular inflammation was abrogated in TLR9(-/-) and macrophage-depleted mice. Bone marrow reconstitution of irradiated TLR9(-/-) mice with TLR9(+/+) bone marrow led to restored corneal inflammatory responses to CpG-ODN. Fluorescein isothiocyanate-CpG-ODN rapidly penetrated the cornea and ocular media to reach the retina, where it was present within CD68(+) retinal macrophages and microglia. These data show that topically applied CpG-ODN induces intraocular inflammation owing to TLR9 activation of monocyte-lineage cells. These novel findings indicate that microbial CpG-DNA released during bacterial and/or viral keratitis can cause widespread inflammation within the eye, including the retina.

| S-EPMC3338340 | biostudies-literature

The effect of TLR9 agonist CpG oligodeoxynucleotides on the intestinal immune response of cobia (Rachycentron canadum).

Project description:Cytosine-guanine oligodeoxynucleotide (CpG ODN) motifs of bacterial DNA are recognized through toll-like receptor 9 (TLR9) and are potent activators of innate immunity. However, the interaction between TLR9 and CpG ODN in aquatic species has not been well characterized. Hence, cobia TLR9 isoform B (RCTLR9B) was cloned and its expression and induction in intestine were investigated. RCTLR9B cDNA consists of 3113bp encoding 1009 amino acids containing three regions, leucine rich repeats, transmembrane domain, and toll/interleukin-1 receptor (TIR) domain. Intraperitoneal injection of CpG ODN 2395 upregulated RCTLR9 A and B and MyD88 and also induced the expressions of Mx, chemokine CC, and interleukin IL-1 ? . Cobia intraperitoneally injected with CpG ODN 1668 and 2395 had increased survival rates after challenge with Photobacterium damselae subsp. piscicida. In addition, formulation of CpG ODN with formalin-killed bacteria (FKB) and aluminum hydroxide gel significantly increased expressions of RCTLR9 A (50 folds) and B (30 folds) isoforms at 10 dpi (CpG ODN 1668) and MyD88 (21 folds) at 6?dpv (CpG ODN 2395). Subsequently, IL-1 ? increased at 6?dpv in 1668 group. No histopathological damage and inflammatory responses were observed in the injected cobia. Altogether, these results facilitate CpG ODNs as an adjuvant to increase bacterial disease resistance and efficacy of vaccines in cobia.

| S-EPMC4060301 | biostudies-literature

A unique nanoparticulate TLR9 agonist enables a HA split vaccine to confer FcγR-mediated protection against heterologous lethal influenza virus infection.

Project description:The development of a universal influenza vaccine that can provide a robust and long-lasting protection against a broader range of influenza virus strains is a global public health priority. One approach to improve vaccine efficacy is to use an adjuvant to boost immune responses to the target antigens; nevertheless, the role of adjuvants in the context of influenza vaccines is not fully understood. We have previously developed the K3-schizophyllan (SPG) adjuvant, which is composed of nanoparticulated oligodeoxynucleotides K3, a TLR9 agonist, with SPG, a non-agonistic β-glucan ligand of Dectin-1. In this study, K3-SPG given with conventional influenza hemagglutinin (HA) split vaccine (K3-SPG HA) conferred protection against antigenically mismatched heterologous virus challenge. While K3-SPG HA elicited robust cross-reactive HA-specific IgG2c and CD8 T-cell responses, CD8 T-cell depletion had no impact on this cross-protection. In contrast, K3-SPG HA was not able to confer protection against heterologous virus challenge in FcRγ-deficient mice. Our results indicated that FcγR-mediated antibody responses induced by the HA antigen and K3-SPG adjuvant were important for potent protection against antigenically mismatched influenza virus infection. Thus, we demonstrated that the K3-SPG-adjuvanted vaccine strategy broadens protective immunity against influenza and provides a basis for the development of next-generation influenza vaccines.

| S-EPMC6599278 | biostudies-literature

Single Cell RNA sequencing of TLR9 ligand (CpG oligonucleotide) and TLR2/4 ligand (LPS)-treated mouse gingiva

Project description:Purpose: The goal of this study was to characterize the gingival oral barrier immunity of TLR9 ligand (CpG oligonucleotide) and TLR2/4 ligand (LPS)-treated mouse maxilla. Method: TLR9 ligand or TLR2/4 ligand was topically applied to the mouse palatal gingiva. Mouse palatal gingiva was harvested at 4 days after topical application. Gingival cells were harvested and subjected to 10X Genomix scRNA-seq. Cell Ranger processed data were analysed.

2022-04-21 | GSE201109 | GEO

TLR9 Ligand (CpG Oligodeoxynucleotide) Induces CLL B-Cells to Differentiate into CD20(+) Antibody-Secreting Cells.

Project description:B-cell chronic lymphocytic leukemia (CLL) is the most frequent adult leukemia in the Western world. It is a heterogeneous disease characterized by clonal proliferation and the accumulation of CD5(+) mature B lymphocytes. However, the normal counterpart from which the latter cells arise has not yet been identified. CD27 expression and gene expression profiling data suggest that CLL cells are related to memory B-cells. In vitro, memory B-cells differentiate into plasma cells when stimulated with CpG oligodeoxynucleotide (CpG). The objective of the present study was therefore to investigate the ability of CpG, in the context of CD40 ligation, to induce the differentiation of CLL B-cells into antibody-secreting cells (ASCs). CD20(+)CD38(-) CLL B-cells were stimulated with a combination of CpG, CD40 ligand and cytokines (CpG/CD40L/c) in a two-step, 7-day culture system. We found that the CpG/CD40L/c culture system prompted CLL B-cells to differentiate into CD19(+)CD20(+)CD27(+)CD38(-)ASCs. These cells secreted large amounts of IgM and had the same shape as plasma cells. However, only IgMs secreted by ASCs that had differentiated from unmutated CLL B-cells were poly/autoreactive. Class-switch recombination (CSR) to IgG and IgA was detected in cells expressing the activation-induced cytidine deaminase gene (AICDA). Although these ASCs expressed high levels of the transcription factors PRDM1 (BLIMP1), IRF4, and XBP1s, they did not downregulate expression of PAX5. Our results suggest that CLL B-cells can differentiate into ASCs, undergo CSR and produce poly/autoreactive antibodies. Furthermore, our findings may be relevant for (i) identifying the normal counterpart of CLL B-cells and (ii) developing novel treatment strategies in CLL.

| S-EPMC4058906 | biostudies-other

Membrane Association Transforms an Inert Anti-TCRβ Fab' Ligand into a Potent T Cell Receptor Agonist.

Project description:The natural peptide-major histocompatibility complex (pMHC) ligand for T cell receptors (TCRs) is inactive from solution yet capable of activating T cells at single-molecule levels when membrane-associated. This distinctive feature stems from the mechanism of TCR activation, which is thought to involve steric phosphatase exclusion as well as direct mechanical forces. It is possible to defeat this mechanism and activate T cells with solution ligands by cross-linking pMHC or using multivalent antibodies to TCR. However, these widely used strategies activate TCRs through a nonphysiological mechanism and can produce different activation profiles than natural, monovalent, membrane-associated pMHC. Here, we introduce a strictly monovalent anti-TCRβ H57 Fab' ligand that, when coupled to a supported lipid bilayer via DNA complementation, triggers TCRs and activates nuclear translocation of the transcription factor nuclear factor of activated T cells (NFAT) with a similar potency to pMHC in primary murine T cells. Importantly, like monovalent pMHC and unlike bivalent antibodies, monovalent Fab'-DNA triggers TCRs only when physically coupled to the membrane, and only around 100 individual Fab':TCR interactions are necessary to stimulate early T cell activation.

| S-EPMC7300389 | biostudies-literature

CD82 controls CpG-dependent TLR9 signaling.

Project description:The tetraspanin CD82 is a potent suppressor of tumor metastasis and regulates several processes including signal transduction, cell adhesion, motility, and aggregation. However, the mechanisms by which CD82 participates in innate immunity are unknown. We report that CD82 is a key regulator of TLR9 trafficking and signaling. TLR9 recognizes unmethylated cytosine-phosphate-guanine (CpG) motifs present in viral, bacterial, and fungal DNA. We demonstrate that TLR9 and CD82 associate in macrophages, which occurs in the endoplasmic reticulum (ER) and post-ER. Moreover, CD82 is essential for TLR9-dependent myddosome formation in response to CpG stimulation. Finally, CD82 modulates TLR9-dependent NF-κB nuclear translocation, which is critical for inflammatory cytokine production. To our knowledge, this is the first time a tetraspanin has been implicated as a key regulator of TLR signaling. Collectively, our study demonstrates that CD82 is a specific regulator of TLR9 signaling, which may be critical in cancer immunotherapy approaches and coordinating the innate immune response to pathogens.-Khan, N. S., Lukason, D. P., Feliu, M., Ward, R. A., Lord, A. K., Reedy, J. L., Ramirez-Ortiz, Z. G., Tam, J. M., Kasperkovitz, P. V., Negoro, P. E., Vyas, T. D., Xu, S., Brinkmann, M. M., Acharaya, M., Artavanis-Tsakonas, K., Frickel, E.-M., Becker, C. E., Dagher, Z., Kim, Y.-M., Latz, E., Ploegh, H. L., Mansour, M. K., Miranti, C. K., Levitz, S. M., Vyas, J. M. CD82 controls CpG-dependent TLR9 signaling.

| S-EPMC6988855 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data