title: Cyclic dinucleotides modulate induced type I IFN responses in innate immune cells by degradation of STING.
abstract: The cyclic dinucleotides, GMP-AMP (cGAMP) and c-di-AMP [bis-(3',5')-cyclic dimeric AMP], are potent type I IFN inducersviaSTING-TBK1-IRF3 cascade. They are promising adjuvants that promote antigen-specific humoral and cellular immune responses in different preclinical models; however, an optimal outcome of vaccination depends on a balanced immune activation. Here, we characterize the process of IFN-β induction by c-di-AMP and cGAMP in anin vitromodel on the basis of primary mouse dendritic cells. Results obtained show decreased IFN-β production upon prolonged cell stimulation. We demonstrate that this effect depends on c-di-AMP/cGAMP-mediated down-regulation of stimulator of IFN gene (STING) protein levels. These results were confirmed by using human peripheral blood mononuclear cell-derived dendritic cells. Studies performed to explore the potential mechanism of STING modulation suggested proteolytic degradation to be a contributing factor to the observed decrease in cellular STING levels. Our work contributes to the elucidation of the molecular mode of action of vaccine constituents, which, in turn, is a prerequisite for the rational design of vaccines with predictable efficacy and safety profiles-Rueckert, C., Rand, U., Roy, U., Kasmapour, B., Strowig, T., Guzmán, C. A. Cyclic dinucleotides modulate induced type I IFN responses in innate immune cells by degradation of STING.
authors.affiliation: Vaccinology Research Group, Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Rueckert
authors.affiliation: Immune Aging and Chronic Infections Research Group, Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Ulfert
authors.initials: U
authors.lastname: Rand
authors.affiliation: Microbial Immune Regulation Research Group, Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Urmi
authors.initials: U
authors.lastname: Roy
authors.affiliation: Immune Aging and Chronic Infections Research Group, Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Bahram
authors.initials: B
authors.lastname: Kasmapour
authors.affiliation: Microbial Immune Regulation Research Group, Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Strowig
authors.affiliation: Vaccinology Research Group, Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany; carlos.guzman@helmholtz-hzi.de.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Guzmán
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D000242:Cyclic AMP / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells; D015536:Down-Regulation; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009712:Nucleotides, Cyclic / Q000494:pharmacology*; D000099197:STING Protein
chemical_list: D000242:Cyclic AMP; D016207:Cytokines; D007370:Interferon Type I; D016899:Interferon-beta; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; C532857:STING1 protein, human; D000099197:STING Protein; C530855:Sting1 protein, mouse; C584311:cyclic guanosine monophosphate-adenosine monophosphate
keywords: adjuvant; immune response; pathogen recognition receptor; regulation inflammatory response; vaccine development