title: Priming MHC-I-restricted cytotoxic T lymphocyte responses to exogenous hepatitis B surface antigen is CD4+ T cell dependent.
abstract: MHC-I (Ld)-restricted, S28-39-specific CTL responses are efficiently primed in H-2d BALB/c mice injected with low doses of native hepatitis B surface Ag (HBsAg) lipoprotein particles without adjuvants. Priming of this CTL response by exogenous HBsAg required CD4+ T cell "help" and IL-12: this CTL response could be neither induced in mice depleted of CD4+ T cells by in vivo Ab treatment, nor in (CD4+ T cell-competent or CD4+ T cell-depleted) IL-12-unresponsive STAT4-/- knockout BALB/c mice. Codelivery of oligonucleotides (ODN) with immunostimulating CpG sequences (ISS) with exogenous 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-depleted 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. CTL priming was not detectable when CD4+ T cell-depleted animals were subjected to genetic immunization. In vivo priming of the well-characterized CD8+ CTL response to HBsAg in "high responder" BALB/c mice either by exogenous surface lipoprotein particles or by DNA vaccination is thus CD4+ T cell dependent. CTL priming by exogenous HBsAg, but not by genetic immunization, 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 this "adjuvants effect" operates efficiently in IL-12-unresponsive mice. The data characterize a feature of the adjuvant effect of ISS-containing ODN on CTL priming that may be of major interest for the design of CTL-stimulating vaccines with efficacy in immunodeficiency conditions.
authors.affiliation: Department of Medical Microbiology, University of Ulm, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Wild
authors.forename: M J
authors.initials: MJ
authors.lastname: Grusby
authors.forename: R
authors.initials: R
authors.lastname: Schirmbeck
authors.forename: J
authors.initials: J
authors.lastname: Reimann
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018899:CpG Islands / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D006183:H-2 Antigens / Q000235:genetics; D006514:Hepatitis B Surface Antigens / Q000008:administration & dosage* / Q000276:immunology*; D017325:Hepatitis B Vaccines / Q000008:administration & dosage / Q000276:immunology; D064532:Histocompatibility Antigen H-2D; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007108:Immune Tolerance / Q000235:genetics; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology; D050797:STAT4 Transcription Factor; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; D064532:Histocompatibility Antigen H-2D; D015395:Histocompatibility Antigens Class I; D009838:Oligodeoxyribonucleotides; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D019444:Vaccines, DNA; D018664:Interleukin-12