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.

Abstract

T cells play a crucial role in antibodymediated 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 PfI55/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 Pfl55/RESA-peptide-specific responses of T cells to function, T cells from P. fakciparum immune donors were activated with peptides corresponding to these immunodominant regions. Activation was measured as induction of interferon-y 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-y, 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 ofserum 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.

Cytokine responses during acute simian Plasmodium cynomolgi and Plasmodium knowlesi infections.

“…Activation of IL-4-producing T cell subsets and production of malaria-specific antibodies have been reported previously. 15 Interleukin-4 is also involved in the induction of isotype switching from IgM to IgG1, IgG4, and IgE. 16 Since type 2 responses are associated with the development of humoral immunity, specifically with antibody isotype switching to IgG1, our observation of greater expression of IL-4 during repeat infection seemed consistent with previous studies.…”

Elevated plasma levels of IgE in Plasmodium falciparum-primed individuals reflect an increased ratio of IL-4 to interferon-gamma (IFN-γ)-producing cells

“…We reported earlier that the P. falciparum blood stage vaccine candidate antigen, Pf155/RESA, stimulates T cells from P. falciparum-primed donors to proliferate, and to produce IFN-g and/or IL-4 [10]. Importantly, in most instances these three activities were not correlated in individual donors.…”

“…In human P. falciparum malaria we have shown earlier that CD4 + T cells from donors primed by natural infection produce IFN-g and/or IL-4 after in vitro exposure to defined malarial peptides. IL-4 production by primed T cells was accompanied by elevated serum levels of antibodies specific for the P. falciparum peptides used for T cell stimulation [10].…”

IgE elevation and IgE anti-malarial antibodies in Plasmodium falciparum malaria; association of high IgE levels with cerebral malaria

“…The formation of these antibodies is controlled by IL-4, produced by CD4' T cells of the Th2 variety [1][2][3]. In human Plasmodium falciparum malaria, we have shown that stimulation of CD4' T cells from immune donors with malaria antigen in vitro frequently induced either IFN-7 or lL-4 secretion, indicating the occurrence of distinct Thl-or Th2-like cells in the blood of these individuals [4]. As IL-4 is involved in switching immunoglobulin isotype production by B cells from IgM to IgE [5][6][7][8] we considered it of interest to investigate the occurrence and possible role of IgE in the development of immunity to P. falciparum malaria.…”