The mucosal adjuvant cyclic di-GMP enhances antigen uptake and selectively activates pinocytosis-efficient cells in vivo

Abstract
Article and author information
Metrics

Abstract

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 T_H 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 T_H 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.

Article and author information

Author details

Steven M Blaauboer

Center for Immunology and Microbial Disease, Albany Medical College, Albany, United States

Competing interests
The authors declare that no competing interests exist.
Samira Mansouri

Center for Immunology and Microbial Disease, Albany Medical College, Albany, United States

Competing interests
The authors declare that no competing interests exist.
Heidi R Tucker

Center for Immunology and Microbial Disease, Albany Medical College, Albany, United States

Competing interests
The authors declare that no competing interests exist.
Hatti L Wang

Center for Immunology and Microbial Disease, Albany Medical College, Albany, United States

Competing interests
The authors declare that no competing interests exist.
Vincent D Gabrielle

Center for Immunology and Microbial Disease, Albany Medical College, Albany, United States

Competing interests
The authors declare that no competing interests exist.
Lei Jin

Center for Immunology and Microbial Disease, Albany Medical College, Albany, United States

For correspondence
JINL@MAIL.amc.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

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.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.