Production by activated human T cells of interleukin 4 but not interferon-gamma is associated with elevated levels of serum antibodies to activating malaria antigens.
T cells play a crucial role in antibody-mediated and antibody-independent immunity against Plasmodium falciparum malaria. Therefore, a vaccine immunogen should include parasite-derived B- and T-cell epitopes capable of giving rise to protective responses in both systems. The P. falciparum antigen Pf155/ring-infected erythrocyte surface antigen (RESA), a vaccine candidate, contains immunodominant T- and B-cell epitopes located in the central (5') and C-terminal (3') invariant repeat regions of the molecule. To relate Pf155/RESA-peptide-specific responses of T cells to function, T cells from P. falciparum immune donors were activated with peptides corresponding to these immunodominant regions. Activation was measured as induction of interferon-gamma secretion, T-cell proliferation (DNA synthesis), or transcription and translation of interleukin 4 (IL-4) mRNA. Peptides from both regions were shown to induce interferon-gamma, IL-4, proliferation, or any combination. In individual donors, there was no correlation between these different activities. Rather, they were negatively correlated, demonstrating the importance of examining multiple parameters of T-cell activation when estimating the proportion of individuals responding to a given epitope. However, IL-4 mRNA and intracellular IL-4 could be induced in T cells of donors who had elevated concentrations of serum antibodies to the same peptide that was used for T-cell activation. These results suggest that a causal relationship exists between the activation of IL-4-producing T-cell subsets and production of the anti-Pf155/RESA-specific antibodies in individuals in which immunity has been induced by natural infection. This finding has implications that should be considered for the selection of immunogens to be included in a future P. falciparum subunit vaccine and for vaccine development in general.
Troye-Blomberg
M
M
Department of Immunology, University of Stockholm, Sweden.
Riley
E M
EM
Kabilan
L
L
Holmberg
M
M
Perlmann
H
H
Andersson
U
U
Heusser
C H
CH
Perlmann
P
P
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology*; D000917:Antibody Formation; D000953:Antigens, Protozoan / Q000276:immunology*; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics*; D004261:DNA Replication; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics; D008213:Lymphocyte Activation; D008288:Malaria / Q000276:immunology*; D008297:Male; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D013936:Thymidine / Q000378:metabolism
D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D012333:RNA, Messenger; D015847:Interleukin-4; D007371:Interferon-gamma; D004247:DNA; D013936:Thymidine