STING pathway stimulation results in a differentially activated innate immune phenotype associated with low nitric oxide and enhanced antibody titers in young and aged mice

• Published in: Vaccine 2019-05, Vol.37 (20), p.2721-2730
• Main Authors: Darling, Ross J., Senapati, Sujata, Kelly, Sean M., Kohut, Marian L., Narasimhan, Balaji, Wannemuehler, Michael J.
• Format: Article
• Language: English
• Subjects: Adjuvant; Adjuvants; Age; Animals; Antibody Formation; Antigen-presenting cells; Antigens; B-Cell Activating Factor - metabolism; BAFF; BLyS protein; Bone marrow; Cell activation; Cyclic dinucleotide; Cytokines - metabolism; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Disease control; Female; Genotype & phenotype; Immune response; Immune system; Immunity, Innate; Immunization; Immunology; Inflammation; Laboratories; Ligands; Lymphocytes; Lymphocytes B; Membrane Proteins - metabolism; Metabolism; Mice; Mitochondria - metabolism; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type II - metabolism; Older people; Phenotype; Phenotypes; Public health; Signal Transduction; Stimulation; STING; TLR agonist; Toll-Like Receptors - agonists; Vaccine; Vaccines
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2019.04.004

•CDNs induce high titer vaccine antibody responses.•STING pathway stimulation leads to innate immune activation with low NO and ROS production.•Low NO production is associated with higher DC secretion of and concentration of serum BAFF.•In vivo inhibition of NO production by a TLR based adjuvant leads to improved antibody responses.•Relative to TLR agonists, CDNs result in high titer antibody responses in aged animals. One of the most concerning public health issues, related to vaccination and disease prevention, is the inability to induce durable immune responses following a single-dose immunization. In this regard, the nature of the inflammatory environment induced by vaccine adjuvants can negatively impact the resulting immune response. To address these concerns, new strategies to vaccine design are needed in order to improve the outcomes of immune responses, particularly in immunologically disadvantaged populations. Comparisons of the scope of innate immune activation induced by TLR agonists versus cyclic dinucleotides (CDNs) was performed. Their effects on the activation characteristics (e.g., metabolism, cytokine secretion) of bone marrow derived dendritic cells (BMDCs) were studied. In addition, the differential effects on in vivo induction of antibody responses were measured. As compared to TLR ligands, the stimulation of BMDCs with CDNs induced distinctly different metabolic outcomes. Marked differences were observed in the production of nitric oxide (NO) and the cytokine BAFF. These distinct differences were correlated with improved (i.e., more rapid and persistent) vaccine antibody responses in both aged and young mice. Our results illustrate that the innate immune pathway targeted by adjuvants can critically impact the outcome of the immune response post-vaccination. Specifically, CDN stimulation of APCs induced an activation phenotype that was characterized by decreased innate effector molecule production (e.g., NO) and increased BAFF. This was attributed to the induction of an innate inflammatory environment that enabled the host to make the most of the existing B lymphocyte potential. The use of adjuvants that differentially engage mechanisms of innate immune activation would be particularly advantageous for the generation of robust, single dose vaccines. The results of this study demonstrated that CDNs induced differential innate activation and enhanced vaccine induced antibody responses in both young and aged mice.