title: The mucosal adjuvant cyclic di-GMP enhances antigen uptake and selectively activates pinocytosis-efficient cells in vivo.
abstract: Effective mucosal adjuvants enhance the magnitude and quality of the vaccine response. Cyclic di-GMP (CDG) is a promising mucosal vaccine adjuvant. However, its in vivo mechanisms are unclear. Here, we showed, in mice, that CDG elicits stronger Ab and TH responses than the mammalian 2'3'-cyclic GMP-AMP (cGAMP), and generated better protection against Streptococcus pneumoniae infection than 2'3'-cGAMP adjuvanted vaccine. We identified two in vivo mechanisms of CDG. First, intranasally administered CDG greatly enhances Ag uptake, including pinocytosis and receptor-mediated endocytosis in vivo. The enhancement depends on MPYS (STING, MITA) expression in CD11C(+) cells. Second, we found that CDG selectively activated pinocytosis-efficient-DCs, leading to T(H) polarizing cytokines IL-12p70, IFNγ, IL-5, IL-13, IL-23, and IL-6 production in vivo. Notably, CDG induces IFNλ, but not IFNβ, in vivo. Our study revealed previously unrecognized in vivo functions of MPYS and advanced our understanding of CDG as a mucosal vaccine adjuvant.
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, United States.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Blaauboer
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, United States.
authors.forename: Samira
authors.initials: S
authors.lastname: Mansouri
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, United States.
authors.forename: Heidi R
authors.initials: HR
authors.lastname: Tucker
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, United States.
authors.forename: Hatti L
authors.initials: HL
authors.lastname: Wang
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, United States.
authors.forename: Vincent D
authors.initials: VD
authors.lastname: Gabrielle
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, United States.
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism*; D000818:Animals; D000941:Antigens / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004705:Endocytosis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000276:immunology; D009712:Nucleotides, Cyclic / Q000276:immunology*; D010873:Pinocytosis / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D016207:Cytokines; D009712:Nucleotides, Cyclic; C584311:cyclic guanosine monophosphate-adenosine monophosphate
keywords: STING; cell biology; dendritic cells; immunology; lung; mouse; mucosal adjuvant; pneumococcal vaccine