Cross-Talk with Myeloid Accessory Cells Regulates Human Natural Killer Cell Interferon-γ Responses to Malaria

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Abstract
Data from a variety of experimental models suggest that natural killer (NK) cells require signals from accessory cells in order to respond optimally to pathogens, but the precise identity of the cells able to provide such signals depends upon the nature of the infectious organism. Here we show that the ability of human NK cells to produce interferon-γ in response to stimulation by Plasmodium falciparum–infected red blood cells (iRBCs) is strictly dependent upon multiple, contact-dependent and cytokine-mediated signals derived from both monocytes and myeloid dendritic cells (mDCs). Contrary to some previous reports, we find that both monocytes and mDCs express an activated phenotype following short-term incubation with iRBCs and secrete pro-inflammatory cytokines. The magnitude of the NK cell response (and of the KIR− CD56bright NK cell population in particular) is tightly correlated with resting levels of accessory cell maturation, indicating that heterogeneity of the NK response to malaria is a reflection of deep-rooted heterogeneity in the human innate immune system. Moreover, we show that NK cells are required to maintain the maturation status of resting mDCs and monocytes, providing additional evidence for reciprocal regulation of NK cells and accessory cells. However, NK cell–derived signals are not required for activation of accessory cells by either iRBCs or bacterial lipolysaccharide. Together, these data suggest that there may be differences in the sequence of events required for activation of NK cells by non-viral pathogens compared to the classical model of NK activation by virus-infected or major histocompatibility complex–deficient cells. These findings have far-reaching implications for the study of immunity to infection in human populations. The outcome of infection is determined both by the ability to limit the initial phase of pathogen colonisation and by the ability to mount an effective adaptive immune response. Both of these processes are influenced by innate immune responses, of which a crucial component can be the ability of natural killer (NK) cells to secrete pro-inflammatory cytokines. Studies in both humans and mice indicate that the magnitude of the early (innate) interferon (IFN)–γ response is a crucial determinant of the outcome of malaria infection. In this study, Newman et al. show that activation of human NK cells by Plasmodium falciparum–infected red blood cells to produce IFN-γ is strictly dependent upon, and regulated by, contact-mediated and soluble (cytokine) signals from two accessory cell populations (myeloid dendritic cells and monocytes). Furthermore, the magnitude of the human NK cell IFN-γ response to P. falciparum–infected red blood cells is highly correlated with levels of expression of co-stimulatory molecules on resting accessory cells. These findings suggest that it might be possible to predict the magnitude of the innate cytokine response, and possibly even susceptibility to malarial disease, from the phenotype of resting monocytes. In addition, these data contribute to the development of a new model of NK activation by non-viral pathogens in which activation of accessory cells precedes, rather than follows, NK activation.

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