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

Steven M Blaauboer,Vincent D Gabrielle,Samira Mansouri,Hatti L Wang,Lei Jin,Heidi R Tucker

doi:10.7554/elife.06670

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.

Highlights

Most pathogens enter the body via mucosal surfaces
We found that Cyclic di-GMP (CDG) enhances Ag uptake in vivo, and selectively activates pinocytosis-efficient DCs in vivo
2′3′-cyclic GMP-AMP (cGAMP) induces stronger type I IFN production than CDG does in mammalian cells (Gao et al, 2013c)

Summary

Introduction

Most pathogens enter the body via mucosal surfaces. Immunization by mucosal routes is more effective at inducing protective immunity against mucosal pathogens than systemic immunization. Only a dozen mucosal vaccines are approved for human use This is largely due to problems with developing safe and effective mucosal adjuvants. Cyclic di-GMP (CDG) is a promising mucosal vaccine adjuvant candidate (Ogunniyi et al, 2008; Hu et al, 2009; Chen et al, 2010; Madhun et al, 2011; Gray et al, 2012). It is ubiquitously found in bacteria, but is absent in higher eukaryotes. CDG is an excellent mucosal vaccine adjuvant candidate promoting both strong humoral and cellular immune responses

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