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.