Protection against malaria by Plasmodium yoelii sporozoite surface protein 2 linear peptide induction of CD4+ T cell- and IFN-gamma-dependent elimination of infected hepatocytes.
Plasmodium falciparum sporozoite surface protein 2 (SSP2), also known as TRAP, is included in experimental human malaria vaccines because Plasmodium yoelii SSP2 is the target of protective CD8+ CTL that eliminate P. yoelii-infected hepatocytes in mice. We now report that immunization with a synthetic branched-chain peptide including four copies of a PySSP2 sequence, NPNEPS, and two tetanus toxin T helper epitopes in the adjuvant TiterMax, or with an 18 amino acid peptide (NPNEPS)3 in the adjuvant protects A/J, but not BALB/c or C57BL/6 mice. Transfer of T lymphocyte-enriched immune splenocytes protects naive mice; in vivo depletion of CD4+ T cells eliminates vaccine-induced protection; and in vivo treatment with anti-IFN-gamma reverses vaccine-induced activity against infected hepatocytes. Lymph node cells from immunized A/J, BALB/c, and C57BL/6 mice recognize the (NPNEPS)3 peptide in vitro. However, the protected A/J mice respond with a predominantly Th1 pattern of lymphocyte response, and the non-protected strains of mice respond with a Th2 pattern. There are many examples of CD4+ T cells transferring protection against infectious organisms. However, to our knowledge, this is the first formal demonstration that immunization with a linear synthetic peptide induces CD4+ T cell-dependent, IFN-gamma dependent, genetically restricted sterile protective immunity against an infectious agent.
The Malaria Program, Naval Medical Research Institute, Bethesda, MD 20889, USA.
R
R
Wang
Y
Y
Charoenvit
G
G
Corradin
P
P
De La Vega
E D
ED
Franke
S L
SL
Hoffman
D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D007114:Immunization; D007371:Interferon-gamma / Q000032:analysis / Q000502:physiology*; D007376:Interleukin-2 / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D008099:Liver / Q000469:parasitology* / Q000473:pathology; D008212:Lymphocyte Depletion; D008288:Malaria / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000276:immunology*; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology*; D010967:Plasmodium yoelii / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000276:immunology*
D007376:Interleukin-2; D017780:Malaria Vaccines; D010446:Peptide Fragments; D015800:Protozoan Proteins; D014614:Vaccines, Synthetic; C076139:sporozoite-surface protein 2, Plasmodium yoelli; D015847:Interleukin-4; D007371:Interferon-gamma