Effective mucosal adjuvants enhance the magnitude and quality of the vaccine response. Cyclic di-GMP is a promising mucosal vaccine adjuvant. However, its in vivo mechanisms are unclear. Here, we showed,in mice, that cyclic di-GMP elicits stronger Ab and TH responses than the mammalian 2'3'-cyclic GMP-AMP, and generated better protection against Streptococcus pneumoniae infection than 2'3'-cyclic GMP-AMP adjuvanted vaccine. We identified two in vivo mechanisms of cyclic di-GMP. First, intranasally administered cyclic di-GMP 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 cyclic di-GMP selectively activated pinocytosis-efficient-DCs, leading to TH polarizing cytokines IL-12p70, IFNγ, IL-5, IL-13, IL-23,and IL-6 production in vivo. Notably, cyclic di-GMP induces IFNλ, but not IFNβ, in vivo. Our study revealed previously unrecognized in vivo functions of MPYS and advanced our understanding of cyclic di-GMP as a mucosal vaccine adjuvant.
Animal experimentation: All experiments with mice were performed in accordance to the regulations and approval of Albany Medical College (Albany, NY) and the Institutional Animal Care and Use Committee, ACUP NO: 1208002.
- Fiona M Powrie, Oxford University, United Kingdom
© 2015, Blaauboer et al.
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