title: Mutating the anchor residues associated with MHC binding inhibits and deviates CD8+ T cell mediated protective immunity against malaria.
abstract: We investigated whether immune responses induced by immunization with plasmid DNA are restricted predominantly to immunodominant CD8+ T cell epitopes, or are raised against a breadth of epitopes including subdominant CD8+ and CD4+ T cell epitopes. Site-directed mutagenesis was used to change one or more primary anchor residues of the immunodominant CD8+ T cell epitope on the Plasmodium yoelii circumsporozoite protein, and in vivo protective efficacy and immune responses against defined PyCSP CD8+ and/or CD4+ epitopes were determined. Mutation of the P2 but not P9 or P10 anchor residues decreased protection and completely abrogated the antigen-specific CD8+ CTL activity and CD8+ dependent IFN-gamma responses to the immunodominant CD8+ epitope and overlapping CD8+/CD4+ epitope. Moreover, mutation deviated the immune response towards a CD4+ T cell IFN-gamma dependent profile, with enhanced lymphoproliferative responses to the immunodominant and subdominant CD4+ epitopes and enhanced antibody responses. Responses to the subdominant CD8+ epitope were not induced. Our data demonstrate that protective immunity induced by PyCSP DNA vaccination is directed predominantly against the single immunodominant CD8+ epitope, and that although responses can be induced against other epitopes, these are mediated by CD4+ T cells and are not capable of conferring optimal protection against challenge.
authors.affiliation: Malaria Program, Naval Medical Research Center, Silver Spring, MD 20910-7500, USA. cdobano@clinic.ub.es
authors.forename: C
authors.initials: C
authors.lastname: Dobaño
authors.forename: A
authors.initials: A
authors.lastname: McTague
authors.forename: A
authors.initials: A
authors.lastname: Sette
authors.forename: S L
authors.initials: SL
authors.lastname: Hoffman
authors.forename: W O
authors.initials: WO
authors.lastname: Rogers
authors.forename: D L
authors.initials: DL
authors.lastname: Doolan
mesh_terms: D000596:Amino Acids / Q000235:genetics; D000818:Animals; D000915:Antibody Affinity / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D000953:Antigens, Protozoan / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation; D016054:DNA, Protozoan / Q000235:genetics; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007109:Immunity / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008288:Malaria / Q000276:immunology*; D051379:Mice; D016296:Mutagenesis / Q000235:genetics*; D050505:Mutant Proteins / Q000276:immunology; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000276:immunology; D010957:Plasmids / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000596:Amino Acids; D000953:Antigens, Protozoan; D016054:DNA, Protozoan; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D050505:Mutant Proteins; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; C067302:liver stage-specific antigen, Plasmodium; D007371:Interferon-gamma