Activation of a Subset of Human NK Cells upon Contact with Plasmodium falciparum-Infected Erythrocytes

Abstract

Human NK cells are the earliest source of the protective cytokine IFN-γ when PBMC from nonimmune donors are exposed to Plasmodium falciparum-infected RBC (iRBC) in vitro. In this study, we show that human NK cells form stable conjugates with iRBC but not with uninfected RBC and that induction of IFN-γ synthesis is dependent on direct contact between the NK cell and the iRBC. NK cells respond to iRBC only in the presence of a source of IL-12/IL-18 and the subset of NK cells that preferentially respond to iRBC express high levels of the lectin-like receptor CD94/NKG2A. There is heterogeneity between donors in their ability to respond to iRBC. DNA analysis has revealed considerable heterogeneity of killer Ig-like receptor (KIR) genotype among the donor population and has identified 21 new KIR allelic variants in the donors of African and Asian descent. Importantly, we find evidence for significant associations between KIR genotype and NK responsiveness to iRBC. This emphasizes the need for large-scale population-based studies to address associations between KIR genotype and susceptibility to malaria.

Innate Immune Responses to Human Malaria: Heterogeneous Cytokine Responses to Blood-Stage Plasmodium falciparum Correlate with Parasitological and Clinical Outcomes

“…This in vivo heterogeneity confirms the relevance of similar findings from in vitro studies (25,36) (K. C. Newman, D. S. Korbel, and E. M. Riley, submitted for publication). Furthermore, data generated from this longitudinal study of prepatent malaria infection have generated a number of novel hypotheses that warrant further investigations in vitro.…”

“…Accordingly, associations have been reported between circulating levels of IL-12 and IL-18 and risk of severe Plasmodium falciparum malaria (14, 16 -21), and, in a prospective epidemiological study, IL-12 production was positively associated with IFN-␥ and TNF-␣ production and negatively associated with parasitemia (22). However, although an essential role has been shown for IL-12 in P. falciparum-induced IFN-␥ production from human PBMC and NK cells (23)(24)(25), it has proved very difficult to detect IL-12 in vitro and little is known of its cellular origins. Evidence also suggests that both TGF-␤ and IL-10 can be produced very rapidly, from innate sources, during murine malaria infections and are required to down-regulate potentially pathogenic inflammatory responses once parasitemia is brought under control (26 -28); however, in both mice and humans, excessive concentrations of TGF-␤ and IL-10 early in infection inhibit type-1 immune responses and thus facilitate parasite growth (29,30).…”

“…The former has allowed the potential role of different cell populations such as dendritic cells (48), ␥␦ T cells (46), and NK cells (24,25,36) to be evaluated; the latter has been useful to uncover associations between immune responses and disease outcome (14, 18 -20) but cannot provide information about the sequence of events between infection and onset of disease. Here, we have taken advantage of experimental, sporozoite-induced malaria infections to describe the kinetics of the systemic cytokine response during the prepatent period of P. falciparum infection in 18 unvaccinated, previously malaria-naive subjects and have compared this with the cytokine responses triggered in vitro from whole blood or PBMC by parasite-infected RBC.…”

“…Furthermore, it is becoming clear that innate responses can differ between individuals (25,36) with potential clinical implications. To date, only two-rather small-studies have exploited the unique opportunity offered by experimental infection of malaria-naive volunteers (during the evaluation of antimalarial vaccines) to study the very early stages of the immune response to malaria (37,38), and it has been difficult to draw any generalizable conclusions from them.…”

Evidence for epistasis between hemoglobin C and immune genes in human P. falciparum malaria: a family study in Burkina Faso

“…33,34 NK cells are among the first blood cells to produce interferon-g in response to P. falciparum-infected red blood cells, and this production requires contact between NK cells and P. falciparuminfected red blood cells. 35,36 The NK receptors and the parasite ligands that are involved in the NK activation are poorly known. Recently, Mavoungou et al 18 reported that NKp30 binds to PfEMP-1 at the surface of infected red blood cells, and that this interaction mediates cytolysis of P. falciparum-infected red blood cells.…”