New MoDC-Targeting TNF Fusion Proteins Enhance Cyclic Di-GMP Vaccine Adjuvanticity in Middle-Aged and Aged Mice

Front Immunol. 2020 Aug 7;11:1674. doi: 10.3389/fimmu.2020.01674. eCollection 2020.

Abstract

Cyclic dinucleotides (CDNs) are promising vaccine adjuvants inducing balanced, potent humoral, and cellular immune responses. How aging influences CDN efficacy is unclear. We examined the vaccine efficacy of 3',5'-cyclic diguanylic acid (cyclic di-GMP, CDG), the founding member of CDNs, in 1-year-old (middle-aged) and 2-year-old (aged) C57BL/6J mice. We found that 1- and 2-year-old C57BL/6J mice are defective in CDG-induced memory T helper (Th)1 and Th17 responses and high-affinity serum immunoglobulin (Ig)G, mucosal IgA production. Next, we generated two novel tumor necrosis factor (TNF) fusion proteins that target soluble TNF (solTNF) and transmembrane TNF (tmTNF) to monocyte-derived dendritic cells (moDCs) to enhance CDG vaccine efficacy in 1- and 2-year-old mice. The moDC-targeting TNF fusion proteins restored CDG-induced memory Th1, Th17, and high-affinity IgG, IgA responses in the 1- and 2-year-old mice. Together, the data suggested that aging negatively impacts CDG vaccine adjuvanticity. MoDC-targeting TNF fusion proteins enhanced CDG adjuvanticity in the aging mice.

Keywords: 3′; 5′-cyclic diguanylic acid (cyclic di-GMP); aging; monocyte-derived dendritic cells (moDCs); tumor necrosis factor (TNF); vaccine.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adjuvants, Immunologic / administration & dosage
  • Adjuvants, Immunologic / pharmacology*
  • Administration, Intranasal
  • Age Factors
  • Aging / immunology
  • Aging / metabolism
  • Animals
  • Cells, Cultured
  • Cyclic GMP / administration & dosage
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / pharmacology
  • Dendritic Cells / drug effects*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Immunity, Mucosal / drug effects
  • Immunization
  • Immunogenicity, Vaccine
  • Immunoglobulin A / immunology
  • Immunoglobulin A / metabolism
  • Immunoglobulin Fc Fragments / administration & dosage
  • Immunoglobulin Fc Fragments / pharmacology*
  • Lung / drug effects*
  • Lung / immunology
  • Lung / metabolism
  • Mice, Inbred C57BL
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / pharmacology*
  • Th1 Cells / drug effects
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Th17 Cells / drug effects
  • Th17 Cells / immunology
  • Th17 Cells / metabolism
  • Tumor Necrosis Factor-alpha / administration & dosage
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Adjuvants, Immunologic
  • Immunoglobulin A
  • Immunoglobulin Fc Fragments
  • Recombinant Fusion Proteins
  • Tumor Necrosis Factor-alpha
  • bis(3',5')-cyclic diguanylic acid
  • Cyclic GMP