Role of IL-2 secreted by PADRE-specific CD4+ T cells in enhancing e7-specific CD8+ T-cell immune responses

CD4(+) T helper cells are known to play an integral role in the generation of CD8(+) T-cell immune responses. We have previously shown that co-administration of DNA vaccines containing E6 or E7 protein of human papillomavirus 16 (HPV-16) combined with DNA encoding invariant (li) chain in which class II- associated Ii peptide ( CLIP) region is replaced with the CD4+ T helper epitope, PADRE (Pan-DR-epitope) (Ii-PADRE DNA) enhanced HPV antigen-specific CD8(+) T-cell immune responses in vaccinated mice. In the current study, we investigated the enhancement of HPV E7- specific CD8(+) T-cell immune responses by PADRE- specific CD4+ T cells. We showed that intradermal administration of li- PADRE DNA at the same location as E7- expressing DNA is necessary to generate strong E7- specific CD8(+) T-cell immune responses. We also showed that PADRE- specific CD4(+) T cells generated by li-PADRE DNA vaccination expressed Th1 cytokine profile. Furthermore, our in vitro study demonstrated that PADRE- specific CD4+ T cells stimulated with PADRE- loaded dendritic cells secrete IL- 2 that leads to the proliferation of E7-specific CD8+ T cells. Thus, our data suggest that activated PADRE- specific CD4+ T helper cells may be required at the vicinity of E7- specific CD8+ T cells where they secrete IL- 2, which enhances the E7- specific CD8+ T-cell immune responses generated by DNA vaccination.