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

Elife. 2015 Apr 21;4:e06670. 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.

Keywords: STING; cell biology; dendritic cells; immunology; lung; mouse; mucosal adjuvant; pneumococcal vaccine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / metabolism*
  • Animals
  • Antigens / metabolism*
  • Cytokines / metabolism*
  • Endocytosis / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mucous Membrane / immunology
  • Nucleotides, Cyclic / immunology*
  • Pinocytosis / immunology

Substances

  • Adjuvants, Immunologic
  • Antigens
  • Cytokines
  • Nucleotides, Cyclic
  • cyclic guanosine monophosphate-adenosine monophosphate