Priming MHC-I-restricted cytotoxic T lymphocyte responses to exogenous hepatitis B surface antigen is CD4(+) T cell dependent

MHC-I (L-d)-restricted, S28-39-specific CTL responses are efficiently prime d in H-2(d) BALB/c mice injected with low doses of native hepatitis B surfa ce Ag (HBsAg) lipoprotein particles without adjuvants, Priming of this CTL response by exogenous HBsAg required CD4(+) T cell "help" and IL-12: this C TL response could be neither induced in mice depicted of CD4(+) T cells by in vivo Ab treatment, nor in (CD4(+) T cell-competent or CD4(+) T cell-depl eted) IL-12-unresponsive STAT4(-/-) knockout BALB/c mice. Codelivery of oli gonucleotides (ODN) with immunostimulating CpG sequences (ISS) with exogeno us HBsAg reconstituted the CTL response to exogenous HBsAg in CD4(+) T cell -depleted normal mice and in CD4(+) T cell-competent and CD4(+) T cell-depl eted STAT4(-/-) BALB/c mice. Injection (by different routes) of "naked" pCI /S plasmid DNA encoding HBsAg into IL-12-responsive or -unresponsive BALB/c mice efficiently primed the MHC-I-restricted, HBsAg-specific CTL response. CTI, priming was not detectable when CD4(+) T cell-depleted animals were s ubjected to genetic immunization. In vivo priming of the well-characterized CD8(+) CTL response to HBsAg in "high responder" BALB/c mice either by exo genous surface lipoprotein particles or by DNA vaccination is thus CD4(+) T cell dependent. CTL priming by exogenous HBsAg, but not by genetic immuniz ation, is IL-12 dependent. The dependence of CTL priming by exogenous HBsAg on CD4+ T cells can be overcome by codelivering ODN with ISS motifs, and t his "adjuvants effect" operates efficiently in IL-12-unresponsive mice. The data characterize a feature of the adjuvant effect of ISS-containing ODN o n CTL priming that may be of major interest for the design of CTL-stimulati ng vaccines with efficacy in immunodeficiency conditions.