Cytokine-facilitated priming of CD8⁺ T cell responses by DNA vaccination

Abstract.

Immune responses elicited by plasmid DNA vaccination can be enhanced and modulated by codelivery of cytokine-encoding plasmids. We studied whether priming of cytotoxic T lymphocyte (CTL) responses against hepatitis B surface antigen (HBsAg) by DNA vaccines injected either intramusculary or intradermally with the gene gun is enhanced by codelivery of cytokine-encoding plasmids. From a panel of tested cytokine plasmids only mouse IFNβ, IL-15, and GM-CSF encoding plasmids showed an effect. Intradermal gene gun vaccination with 1 µg plasmid DNA encoding intracellular HBsAg (large LS) showed enhanced CTL priming when IFNβ, IL15, or GM-CSF encoding plasmids were codelivered; this was not observed when a DNA vaccine encoding secreted HBsAg (small S) was injected. Intramuscular injection of low (5 µg) doses of a DNA vaccine encoding large HBsAg did not prime CTL when delivered without cytokines, with IFNβ or IL15-encoding plasmids. However, codelivery with GM-CSF encoding plasmid DNA primed potent, specific CTL immunity detected either in a cytotoxic assay or by determining the frequency of L^d-restricted CD8⁺ T cells specifically inducible to IFNγ production. The codelivery of GM-CSF encoding plasmids with the DNA vaccine furthermore enhanced CTL priming to a subdominant, D^d-restricted epitope of HBsAg. The adjuvant effect of cytokine-encoding plasmids on CTL priming by DNA vaccines is thus complex and depends on: (a) the type of cytokine (or combination of cytokines) codelivered, (b) the type (intracellular vs. secreted) and dose (1–50 µg) of the DNA vaccine, (c) the method of DNA vaccine delivery ("naked" vs. particle-coated DNA), and (d) the (intramuscular vs. intradermal) route of delivery of the DNA vaccine.