Sequential administration of cytokine genes to enhance cellular immune responses and CD4 (+) T memory cells during DNA vaccination.

Antigen specific memory T cells (Tm) have shown to be an important factor in protecting hosts against subsequent infection by previously encountered pathogens. During T-cell activation, several cytokines including IL-6, IL-7 and IL-15, play crucial roles in the development of T cells into memory T cells. With the aim of generating specific Tm, we examined a strategy of sequential administration of molecular adjuvants. In this strategy a DNA vaccine encoding the VP1 capsid protein of foot and mouth disease virus (designated pcD-VP1) was co-delivered to mice along with an IL-6 expressing plasmid (pVAX-IL-6) as an initial molecular adjuvant and boosted with either an IL-7 or IL-15 expressing plasmid, (pVAX-IL-7 or proVAX-IL-15) as the secondary adjuvant. During the pcD-VP1 immunization, we demonstrated that the groups primed with IL-6 and boosted with either IL-7 or IL-15 resulted in the enhancement of cellular and humoral immune responses, maturation of dendritic cells (DCs) and macrophages, and a higher frequency of CD4 (+) Tm (characterized by expressing CD44 (high) CD62L (low) markers, compared with the other groups). Thus, we took advantage of the different effects of cytokines on T cell development, not only to induce a higher level of immune responses after vaccination, but also to generate a higher ratio of CD4 (+) Tm in this sequential cytokine prime-boost study. This would then lead to the mounting of an effective long-term antigen specific immune response.