title: CD4+ T cells acting independently of antibody contribute to protective immunity to Plasmodium chabaudi infection after apical membrane antigen 1 immunization.
abstract: Apical membrane Ag 1 (AMA1) is a leading malaria vaccine candidate. Homologues of AMA1 can induce protection in mice and monkeys, but the mechanism of immunity is not understood. Mice immunized with a refolded, recombinant, Plasmodium chabaudi AMA1 fragment (AMA1B) can withstand subsequent challenge with P. chabaudi adami. Here we show that CD4+ T cell depletion, but not gammadelta T cell depletion, can cause a significant drop in antiparasite immunity in either immunized normal or immunized B cell KO mice. In normal mice, this loss of immunity is not accompanied by a decline in Ab levels. These observations indicate a role for AMA1-specific Ab-independent T cell-mediated immunity. However, the loss of immunity in normal CD4+ T cell-depleted mice is temporary. Furthermore, immunized B cell KO mice cannot survive infection, demonstrating the absolute importance of B cells, and presumably Ab, in AMA1-induced immunity. CD4+ T cells specific for a cryptic conserved epitope on AMA1 can adoptively transfer protection to athymic (nu/nu) mice, the level of which is enhanced by cotransfer of rabbit anti-AMA1-specific antisera. Recipients of rabbit antisera alone do not survive. Some protected recipients of T cells plus antisera do not develop their own AMA 1-specific Ab response, suggesting that AMA 1-specific CMI alone can protect mice. These data are the first to demonstrate the specificity of any protective CMI response in malaria and have important implications for developing a malaria vaccine.
authors.affiliation: Cooperative Research Centre for Vaccine Technology, Queensland Institute of Medical Research, Royal Brisbane Hospital, Brisbane, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.forename: A N
authors.initials: AN
authors.lastname: Hodder
authors.forename: H
authors.initials: H
authors.lastname: Yan
authors.forename: P E
authors.initials: PE
authors.lastname: Crewther
authors.forename: R F
authors.initials: RF
authors.lastname: Anders
authors.forename: M F
authors.initials: MF
authors.lastname: Good
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis / Q000502:physiology*; D000918:Antibody Specificity; D000953:Antigens, Protozoan / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D007106:Immune Sera / Q000008:administration & dosage; D007113:Immunity, Innate; D007274:Injections, Intraperitoneal; D008212:Lymphocyte Depletion; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D008288:Malaria / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology*; D008565:Membrane Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008969:Molecular Sequence Data; D018512:Parasitemia / Q000276:immunology / Q000517:prevention & control; D016788:Plasmodium chabaudi / Q000235:genetics / Q000276:immunology*; D015800:Protozoan Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D018984:Epitopes, T-Lymphocyte; D007106:Immune Sera; D017780:Malaria Vaccines; D008565:Membrane Proteins; D015800:Protozoan Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014614:Vaccines, Synthetic; C090077:apical membrane antigen I, Plasmodium