The Role of the cGAS-Sting Pathway in DNA Vaccination and Autoimmune Disease

The innate immune system recognizes certain molecular patterns expressed by pathogens via pattern recognition receptors (PRR). As a PRR, cyclic GMP-AMP synthase (cGAS) functions as a cytosolic DNA sensor. Stimulator of Interferon Genes (STING) functions as the downstream adaptor protein. Activation of the cGAS-STING pathway results in proinflammatory cytokine production. Here I show that the cGAS-STING pathway plays dual roles in mediating DNA adjuvant activity and the use of 2'3'-cyclic GMP-AMP (cGAMP) as a vaccine adjuvant in mice, in addition to promoting autoantibody production and autoimmune inflammatory cell accumulation in lupus-prone mice. It is unclear which DNA sensor is responsible for mediating the adjuvant effects of plasmid DNA during the course of DNA vaccination. I show that the cGAS-STING pathway is required for generation of antigen-specific immune responses following DNA-adjuvanted vaccination. Mice vaccinated with influenza antigens co-administered with 2'3'-cGAMP develop robust neutralizing antibody titers, enhanced antigen-specific CD8+ T-cell responses, and are protected against lethal influenza virus challenge. The efficacy of 2'3'-cGAMP as a vaccine adjuvant can be enhanced by liposome-assisted delivery, the use of non-hydrolyzable analogs, or co-administration with CpG-C DNA. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. The exact etiology of SLE is unclear, but work utilizing mouse models of SLE have shown that the PRRs of the innate immune system contribute to disease pathogenesis. My results show that in C57BL/6J-Faslpr/Faslpr mice, genetic ablation of cGAS or STING significantly decreases antinuclear autoantibody titers as well as a number of autoimmune inflammatory cell populations. These results are dependent on the genetic background of the mice, as genetic ablation of cGAS or STING in B6.MRL/Mp-Faslpr/Faslpr mice or B6.Sle1-Faslpr/Faslpr mice does not recapitulate the phenotype of cGAS-/- or STING gt/gt.C57BL/6J-Faslpr/Faslpr mice. My results provide more insight into the innate immune mechanisms involved in DNA vaccination and show that 2'3'-cGAMP promotes the enhanced development of protective immune responses, thereby demonstrating the potential utility of 2'3'-cGAMP as a molecular adjuvant for vaccines. Furthermore, my results demonstrate that the cGAS-STING pathway contributes to autoimmune disease development in C57BL/6J-Faslpr/Faslpr mice and implicates cGAS or STING as potential therapeutic targets for the treatment of SLE.