Enhanced immunostimulatory activity of cyclic dinucleotides on mouse cells when complexed with a cell-penetrating peptide or combined with CpG

Yildiz, S.
Alpdundar, E.
Gungor, B.
Kahraman, T.
Bayyurt, B.
Gursel, I.
Gursel, M.
Source Title
European Journal of Immunology
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Electronic ISSN
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.

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Book Title
Arginine peptide (nona-arginine) , CGAMP , CpG ODN , Cyclic-di-GMP , Immunostimulation , Alpha interferon , Arginine , Bacterial protein , Beta interferon , CD11b antigen , CD14 antigen , CD45 antigen , CD86 antigen , Cell penetrating peptide , CpG oligodeoxynucleotide , Cyclic diguanosine monophosphate , Dinucleotide , DNA , Fluorescent dye , Gamma interferon inducible protein 10 , Glycoprotein p 15095 , Immunostimulating agent , Interferon , Interleukin 12 , Interleukin 6 , Lipofectamine , Major histocompatibility antigen class 2 , Ovalbumin , Toll like receptor 9 , Trypan blue , Tumor necrosis factor alpha , Unclassified drug , Bis(3',5')-cyclic diguanylic acid , Cell penetrating peptide , CPG-oligonucleotide , Cyclic GMP , Cyclic guanosine monophosphate-adenosine monophosphate , Cyclic nucleotide , Cytokine , Immunological adjuvant , Interferon , Membrane protein , MPYS protein, mouse , Oligodeoxyribonucleotide , Peptide , Animal cell , Animal experiment , Animal model , Antigen presenting cell , Article , Cell maturation , Cellular immunity , Complex formation , Controlled study , Cytokine production , Cytokine release , Drug potentiation , Human , Human cell , Immunostimulation , Innate immunity , Internalization , Low drug dose , Mouse , Nonhuman , Normal human , Peripheral blood mononuclear cell , Priority journal , Spleen cell , Tumor volume , Upregulation , Analogs and derivatives , Animal , Biosynthesis , C57BL mouse , Chemistry , CpG island , Cytology , Drug effects , Spleen , Tumor cell culture , Adjuvants, Immunologic , Animals , Cell-Penetrating Peptides , CpG Islands , Cyclic GMP , Cytokines , Humans , Immunity, Innate , Interferon Type I , Membrane Proteins , Mice , Mice, Inbred C57BL , Nucleotides, Cyclic , Oligodeoxyribonucleotides , Peptides , Spleen , Tumor Cells, Cultured
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