In vitro cell-mediated immune responses to Plasmodium falciparum schizont antigens in adults from a malaria endemic area: CD8⁺ T lymphocytes inhibit the response of low responder individuals

Abstract

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)

Lymphoproliferative responses to a merozoite surface antigen of Plasmodium falciparum: preliminary evidence for seasonal activation of CD8+/HLA-DQ-restricted suppressor cells

“…Taken together, these results suggest that CCD8^) DQrestricted cells may be activated during periods of malaria transmission to down-regulate the cellular proliferative response to PfMSPI, Seasonal variation in thesuppressiveeffects of CD8' cells has been reported previously [8] (CD8' eells isolated from malaria-exposed donors during the malaria transmission season had suppressive activity whereas cells isolated in the dry season did not), but ttie only other study of DQ-medialed suppression of responses to malaria antigens [7] was conducted in an area of year-round malaria transmission where sueh seasonal changes would nol be expected.…”

“…Previous studies have indicated that in some malariaimmune donors proliferative responses to crude schi/ont anligen pteparatiiins can be enhanced by removal of the CD8* lymphoeyle population from the culture system [6][7][8][9], but the effect of CD8' depletion on responses to defined malaria antigens has not been investigated. We have examined ibe phcEUit) pc of cells proHlerating in response to one such antigen, PfMSPI, The responding cell population appears lobe predominantly CD4' and HLA-DR-restricted, but a smaller population of CD8 ' eells -which may be HLA-DQ restricted can also respond.…”

“…I-dinburgh F.H9 .1JT. UK, term exposure to Plasmodium Jalciparum or P. vivux [4,5], Pcripheri.il blood mononuclear eells (PBMC) from a proportion of apparently immune individuals arc non-responsive lo crude or partially purilied schizoni extracts, bul noii-responsiveness caji be reversed by removal of CD8' cells from the PBMC population [6][7][8][9]. Il has also been suggested thai blocking HLA-DQ molecules on the surface of antigen-presenting cells will reverse non-responsiveness to malaria antigens [7), A simitar phenomenon of HLA-DQ-associated T cell non-responsiveness has been described for the human immtine response to Schisto-.…”

Taenia crassiceps cysticercosis: A role for prostaglandin E2 in susceptibility

“…It is well known that a number of diverse parasitic species such as Toxoplasma (Susuki and Kobayashi 1981), Plasmodium (Mshana et al 1990), Trypanosoma (Tarleton 1988;Silva et al 1992), and Leishmania (Proudfoot et al 1995) exert an immunomodulatory activity causing potentially host-protective eector responses to be down-regulated. These anomalies are related to disturbances in the production and utilization of IL-2, activation of CD8+ suppressor T cells and the generation of indomethacin sensitive suppressor mechanisms.…”

In vitro lymphoproliferative responses to malaria antigens: a prospective study of residents of a holoendemic area with perennial malaria transmission

“…fulcipurum SGE-2 Zairean strain was grown in vitro and when parasitaemia reached 10-12%, schizonts were isolated by centrifugation over 55% Percoll. A soluble extract (Pf SE) was prepared from schizonts as described earlier (Mshana, McLean & Boulandi 1990). Control antigen was similarly prepared using uninfected human red blood cells.…”