Mechanisms Underlying Early Interferon‐γ Production in HumanPlasmodium falciparumMalaria

To the Editor—Our longitudinal field study investigated associations of interferon-γ (IFN-γ) with risk of malaria disease [1], not the mechanisms by which this effector cytokine is regulated. However, Dr. Torre [2] has raised an interesting discussion with regard to the upstream pathways leading to the production of IFN-γ. It is well-known that, in many disease systems, interleukin (IL)–12 and IL-18 are potent proinflammatory, immunomodulatory cytokines that induce IFN-γ. Certainly, in malaria, natural killer (NK) cells require accessory signals from IL-12 and IL-18, as well as from IFN-α and IL-2, for optimal IFN-γ production in response to Plasmodium falciparum [3–5]. However, accessory cytokine signals alone are not sufficient for optimal IFN-γ production by NK cells, with contact-dependent signals from macrophages, myeloid dendritic cells, and P. falciparum–infected red blood cells (iRBCs) also being required [4–7]. Unlike NK cells, γδ-T cells—which are the major cellular source of iRBC-induced IFN-γ in humans [8, 9]—do not require accessory cells or cytokines for IFN-γ production in response to P. falciparum antigens [10]. Nonetheless, as would be expected, IFN-γ responses are increased when γδ-T cells are cultured in the presence of both P. falciparum antigens and accessory cytokines [10]. Importantly, in contrast to Dr. Torre's [2] suggestion, NK cells are not required to activate γδ-T cells, nor are they required to “kick-start” the inflammatory response, because depletion of NK cells has no effect on IFN-γ production by γδ-T cells or on the overall IFN-γ response within the first 24 h of exposure to iRBCs [8]. The existing evidence thus shows that, although accessory cytokines, such as IL-12, IL-18, IFN-α, and IL-2, are important for augmenting P. falciparum–induced IFN-γ responses by NK cells and γδ-T cells, other pathways are clearly involved. Accordingly, the activating ligand for γδ-T cells is known to be a P. falciparum nonpeptide phosphoantigen (possibly [E]-4-hydroxy-3-methyl-but-2-enyl diphosphate) that appears to bind directly to the γδ-T cell receptor during innate γδ-T cell activation [10–12]. The parasite ligands and host receptors involved in contact-dependent NK cell activation remain to be elucidated; however, NK cell activation primarily occurs through a major group of receptors known as NK receptors. These include killer immunoglobulin-like receptors, natural cytotoxicity receptors, Siglec-7, and members of the C-type lectin family, such as the NKG2 receptors [13]. Therefore, it is likely that at least some of these receptors may be involved in iRBC-mediated induction of IFN-γ from NK cells. γδ-T cells also express NK receptors, thus providing an additional pathway that may be involved in the regulation of IFN-γ production by this cell population. Dr. Torre [2] proposes that IL-12 and IL-18 are the key factors determining the overall magnitude or heterogeneity of the IFN-γ response observed in malaria-naive and malaria-exposed individuals [1, 3, 7, 8]. This hypothesis has been previously explored by Artavanis-Tsakonas et al. [3], who found that, although IL-12 and IL-18 are important for the production of IFN-γ, the addition of recombinant IL-12 and IL-18 did not induce higher IFN-γ production from low responders, and these cytokines alone were not sufficient to account for the malaria-specific heterogeneity in IFN-γ responses among individuals [3]. The mechanisms underlying malaria-specific heterogeneity in early IFN-γ responses remain to be elucidated. Host genetic factors may be involved; in support of this, we found that expression of the pan-NK marker CD56 on malaria-responsive γδ-T cells correlated with the magnitude of IFN-γ responses in semi-immune Papua New Guinean children [1]. Similarly, in malaria-naive individuals, expression of the NK complex–encoded receptor CD94 on γδ-T cells correlated with IFN-γ output [8]. Thus, NK-receptor expression on NK-like γδ-T cells (and possibly NK cells) may partially control IFN-γ responsiveness to P. falciparum, as does NK-receptor expression in Plasmodium berghei murine malaria [14, 15]. Parasite factors, such as P. falciparum erythrocyte membrane-1, which negatively regulates early IFN-γ production [16], may also be involved, as well as other factors, such as age and previous exposure to P. falciparum. Potential conflicts of interest.All authors: no conflicts.