Enhanced immunostimulatory activity of cyclic dinucleotides on mouse cells when complexed with a cell-penetrating peptide or combined with CpG
European Journal of Immunology
Wiley - V C H Verlag GmbH & Co. KGaA
1170 - 1179
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Recognition of pathogen-derived nucleic acids by immune cells is critical for the activation of protective innate immune responses. Bacterial cyclic dinucleotides (CDNs) are small nucleic acids that are directly recognized by the cytosolic DNA sensor STING (stimulator of IFN genes), initiating a response characterized by proinflammatory cytokine and type I IFN production. Strategies to improve the immune stimulatory activities of CDNs can further their potential for clinical development. Here, we demonstrate that a simple complex of cylic-di-GMP with a cell-penetrating peptide enhances both cellular delivery and biological activity of the cyclic-di-GMP in murine splenocytes. Furthermore, our findings establish that activation of the TLR-dependent and TLR-independent DNA recognition pathways through combined use of CpG oligonucleotide (ODN) and CDN results in synergistic activity, augmenting cytokine production (IFN-α/β, IL-6, TNF-α, IP-10), costimulatory molecule upregulation (MHC class II, CD86), and antigen-specific humoral and cellular immunity. Results presented herein indicate that 3′3′-cGAMP, a recently identified bacterial CDN, is a superior stimulator of IFN genes ligand than cyclic-di-GMP in human PBMCs. Collectively, these findings suggest that the immune-stimulatory properties of CDNs can be augmented through peptide complexation or synergistic use with CpG oligonucleotide and may be of interest for the development of CDN-based immunotherapeutic agents.
KeywordsArginine peptide (nona-arginine)
Cell penetrating peptide
Cyclic diguanosine monophosphate
Gamma interferon inducible protein 10
Glycoprotein p 15095
Major histocompatibility antigen class 2
Toll like receptor 9
Tumor necrosis factor alpha
Bis(3',5')-cyclic diguanylic acid
Cell penetrating peptide
Cyclic guanosine monophosphate-adenosine monophosphate
MPYS protein, mouse
Antigen presenting cell
Low drug dose
Peripheral blood mononuclear cell
Analogs and derivatives
Tumor cell culture
Interferon Type I
Mice, Inbred C57BL
Tumor Cells, Cultured
Published Version (Please cite this version)http://dx.doi.org/10.1002/eji.201445133
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