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

• Published in: Vaccine 2022-11, Vol.40 (50), p.7270-7279
• Main Authors: Fisher, Devin G., Gnazzo, Victoria, Holthausen, David J., López, Carolina B.
• Format: Article
• Language: English
• Subjects: Adjuvant; Adjuvants; Adjuvants, Immunologic; Animals; Antigens; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes; Cloning; Cytokines; Defective viral genome-derived oligonucleotide (DDO); Dendritic cells; Dendritic Cells - immunology; Effector cells; Flow cytometry; Genome, Viral; Genomes; Infections; Inflammation; Influenza; Injection; Interferon; Interferon Type I - metabolism; Intracellular; Laboratory animals; Lymph nodes; Lymphatic system; Lymphocytes T; Mice; Monoclonal antibodies; Oligonucleotides; Pandemics; Pathogens; Poly I-C; Polyinosinic:polycytidylic acid; RNA, Viral; Statistical analysis; TLR3 protein; Toll-Like Receptor 3; Toll-like receptors; Type 1 immunity; Type I interferon; Vaccination; Vaccine; Vaccines; Virus; Viruses
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2022.10.052

•DDO generates a local type I IFN and inflammatory response.•DDO induces accumulation of cDC1s in the draining lymph node.•Response is not identical to Poly:IC, a known TLR3 sensor and Type I IFN stimulator.•Type I IFN signaling and TLR3 mediate DDO induced cDC1 accumulation.•Loss of cDC1s in draining LNs stops development of antigen specific CD8 + T cells. 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 defective viral genome-derived oligonucleotides (DDOs) as novel adjuvants that strongly induce 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 Toll-like receptor 3 (TLR3)- and 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, DDOs induced an inflammatory cytokine profile distinct from that induced by poly I:C. Therefore, DDOs represent a powerful new adjuvant to be used during vaccination against intracellular pathogens.