Mucosal vaccine adjuvant cyclic di-GMP induces STING-dependent pulmonary dendritic cell activation

Abstract

Abstract The mucosal surface is the major entry site for many human pathogens, however there are only a dozen of mucosal vaccines approved for human use. The challenge for mucosal vaccines is to develop safe and effective mucosal adjuvants. 3′, 5′-Cyclic di-GMP (CDG) is an attractive mucosal vaccine adjuvant candidate that activates STING (stimulator of interferon genes). However, the in vivo mechanism of action of CDG is not completely understood. Our previous studies found that intranasal immunization with CDG directly activates pulmonary dendritic cells (DCs). We found that CDG adjuvant activity depends on TNFα and not type I interferon. Deletion of STING in pulmonary DCs resulted in the reduction of antigen-specific antibodies and a decrease in Th1/Th2/Th17 responses. Here, we investigated the role of different pulmonary DCs subsets in mediating the mucosal adjuvant activity of CDG. Our results demonstrate that CDG targets unique and specialized functions of pulmonary DC subsets. Using Batf3−/− mice to deplete CD103+ DCs, we found that CD103+ DCs do not mediate the CDG-induced antibody production, but are needed for Th responses as well as the recruitment of the novel CD103+CD11b+ pulmonary DC population. The population of pulmonary CD11b+ DCs was intact in the Batf3−/− mice. CDG-induced humoral immunity completely depends on pulmonary DCs. Our data, thus, suggested that CD11b+ DCs, which were the only pulmonary DCs not depleted in Batf3−/− mice, were sufficient for CDG-induced humoral immunity. How STING mediates CDG responses in these DC subsets will be discussed. Understanding the role of different DC subsets will reveal insight in the mode of action of CDG in vivo and advance the development of CDG as an efficacious mucosal vaccine adjuvant.