Figure 4

Proposed mechanism of the adjuvant activity of the cytolytic DNA vaccine. (A) It is favourable to deliver DNA vaccines into the dermis because it is rich in DCs, but the vast majority of the dermis is composed of fibroblasts and keratinocytes making them the main targets for DNA uptake. Following expression, 12del PRF expression in cytolytic DNA transfected cells will cause necrotic cell death leading to sterile inflammation, and exposure of intrinsic cell DAMPs and vaccine antigens to DCs. Dermal DCs, including those recruited from other anatomical sites due to sterile inflammation, will endocytose the antigen and be exposed to DAMPs resulting in maturation (up-regulation of CD80/CD86 expression). Thus DCs, the most efficient antigen cross-presenting cells in vivo, will in this instance efficiently prime naïve CD8⁺ T cells. This is a time-dependent process and likely depends on the accumulation of antigen and DAMPs at the dermis due to prolonged expression of cytolytic DNA in fibroblasts and keratinocytes. (B) Conversely, canonical DNA vaccines are unlikely to result in significant cell death and mainly rely on directly targeting DCs in the dermis and to some extent cross-presentation of transfected dead cells and transferred/shed antigens. Hence, canonical DNA vaccination is less efficient in priming naïve CD8⁺ T cells than cytolytic DNA vaccination.