Plasmodium falciparum schizont extract and purified protein derivative were used to stimulate peripheral blood mononuclear cells obtained from healthy aparasitemic Gabonese individuals with lifelong exposure to malaria infection and non-Gabonese control subjects who have had had no clinical malaria. In vitro lymphoproliferation was measured by uptake of tritiated thymidine, while production of interleukin-2, interferon-gamma, and soluble CD8+ were measured by immunoenzymatic assays. Enumeration of interferon-gamma-producing cells was done using a modified immunoenzyme spot assay. Twenty-eight percent of Gabonese subjects were determined to be low responders in the lymphoproliferative assay, with a tritiated thymidine uptake of less than 6000 c.p.m. The proportions of T cell subsets and the kinetics of the proliferative response were similar in the low and the high responders. Removal of CD8+ T cells from mononuclear cells of low responders or culture of purified CD4+ T cells from the same individuals resulted in a 7-fold increase in the proliferative response to the schizont antigen but not to purified protein derivative (PPD). A similar increase in the proliferative response was seen in the low but not the high responder mononuclear cell cultures stimulated with the schizont antigen in the presence of exogenous interleukin 2 (IL-2) or in the presence of anti-HLA-DQ antibody. Low responder mononuclear cell cultures stimulated with schizont antigen but not PPD produced 3-fold less IL-2, 14-fold less interferon-gamma (IFN-gamma), and 3-fold more soluble CD8 than high responder mononuclear cell cultures. Removal of CD8+ T cells from low responder mononuclear cells resulted in a 2-fold increase in IL-2 production and a 4-fold increase in IFN-gamma production in response to schizont antigen. High responder mononuclear cells stimulated with schizont antigen contained four times as much IFN-gamma-producing cells as low responder cultures, with each IFN-gamma-producing cell producing three times the amount of IFN-gamma as that produced by an IFN-gamma-producing cell in low responder cultures. Removal of CD8+ T cells from low responder mononuclear cells led to a significant increase in the amount of IFN-gamma produced at the single cell level in response to schizont antigen stimulation. In such cultures, the amount of IFN-gamma produced by a single cell was similar between high and low responders. We conclude that in certain individuals, T cell responses to schizont antigen are actively down-regulated by activated schizont-specific CD8+ suppressor T cells.(ABSTRACT TRUNCATED AT 400 WORDS)

A longitudinal, prospective study to examine the relationship between the outcome of infection with Plasmodium falciparum parasites and in vitro T-cell proliferative responses to a P. falciparum schizont extract (PfSE) was conducted in a village in south-eastern Gabon, an area where malaria is holoendemic and transmission is intense and perennial. The donor's age was found to have a strong independent influence on all malariometric indices. At the community level, the in vitro lymphoproliferative response to PfSE was bimodal with 30% of the villagers studied showing persistently low responses. The frequency of low or high responders within the study population did not show any consistent relationship with the community parasite rates or the number of either patent parasitaemic episodes or clinical malarial attacks per individual. At the individual donor level, the response was negatively correlated with P. falciparum parasite density in those donors who were parasitaemic at the time of sampling. High in vitro lymphoproliferative responses to PfSE were predictive of resistance to clinical malaria. The PfSE-induced in vitro lymphoproliferative response was dependent on antigen presenting cells, CD4+ T-cells and UCHL-1+ cells.