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Non-standard viral genome-derived RNA activates TLR3 and type I IFN signaling to induce cDC1-dependent CD8+ T-cell responses during vaccination in mice

There is a critical need to develop vaccine adjuvants that induce robust immune responses able to protect against intracellular pathogens, including viruses. Previously, we described the virus-derived adjuvant, defective viral genome-derived oligonucleotide (DDO), as a strong inducer of type 1 immune responses, including protective Th1 CD4+ T-cells and effector CD8+ T-cells in mice. Here we unravel the early innate response required for this type 1 immunity induction. Upon DDO subcutaneous injection, type 1 conventional dendritic cells (cDC1s) accumulate rapidly in the draining lymph node in a type I interferon (IFN)-dependent manner. cDC1 accumulation in the lymph node is required for antigen-specific CD8+ T-cell responses. Notably, in contrast to poly I:C, DDO administration resulted in type I IFN expression at the injection site, but not in the draining lymph node. Additionally, DDO induced an inflammatory cytokine profile distinct from that induced by poly I:C. Therefore, DDO represent a powerful new adjuvant to be used during vaccination against intracellular pathogens. IMPORTANCE There is a paucity of vaccine adjuvants able to trigger effective and safe protective responses to many intracellular pathogens. Defining the minimal requirements to achieve type 1 immunity, which includes antigen specific CD8+ T cells capable of eliminating infected cells, is essential for the development of adjuvants that lead to optimal protective immune responses during vaccination against intracellular pathogens. We use a virus-derived immunostimulatory molecule, defective viral genome-derived oligonucleotide (DDO), to provide insights into how type 1 immune responses are triggered during vaccination using an inactivated influenza vaccine model. Understanding the mechanism of action of vaccine adjuvants not only aids in the advancement of vaccine development, but also in understanding specific immune pathways required for efficient induction of adaptive immune responses to infections.