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.
Copyright © 2020 Gogoi, Mansouri, Katikaneni and Jin.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
MeSH terms
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Adjuvants, Immunologic / administration & dosage
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Adjuvants, Immunologic / pharmacology*
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Administration, Intranasal
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Age Factors
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Aging / immunology
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Aging / metabolism
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Animals
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Cells, Cultured
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Cyclic GMP / administration & dosage
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Cyclic GMP / analogs & derivatives*
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Cyclic GMP / pharmacology
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Dendritic Cells / drug effects*
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Immunity, Mucosal / drug effects
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Immunization
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Immunogenicity, Vaccine
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Immunoglobulin A / immunology
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Immunoglobulin A / metabolism
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Immunoglobulin Fc Fragments / administration & dosage
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Immunoglobulin Fc Fragments / pharmacology*
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Lung / drug effects*
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Lung / immunology
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Lung / metabolism
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Mice, Inbred C57BL
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Recombinant Fusion Proteins / administration & dosage
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Recombinant Fusion Proteins / pharmacology*
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Th1 Cells / drug effects
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Th17 Cells / drug effects
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Th17 Cells / immunology
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Th17 Cells / metabolism
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Tumor Necrosis Factor-alpha / administration & dosage
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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Adjuvants, Immunologic
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Immunoglobulin A
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Immunoglobulin Fc Fragments
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Recombinant Fusion Proteins
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Tumor Necrosis Factor-alpha
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bis(3',5')-cyclic diguanylic acid
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Cyclic GMP