Whatever turns you on: accessory-cell-dependent activation of NK cells by pathogens

Key Points Natural killer (NK)-cell activation by most pathogens is strictly dependent on the presence of accessory cells, such as monocytes, macrophages or dendritic cells. Direct contact with accessory cells is required for optimal NK-cell responses to most pathogens, and the molecular interactions that underlie this are beginning to be unravelled. Multiple accessory-cell-derived cytokines — both pro-inflammatory and anti-inflammatory — influence NK-cell responses to pathogens. The precise identity of the accessory cell that mediates NK-cell activation varies from one class of pathogen to another, depending on which accessory cell expresses the appropriate pathogen-recognition receptors for the different classes of pathogen-derived ligands. NK cells can pass reciprocal activating signals to accessory cells; however, the physiological relevance of such bidirectional interactions might depend on the nature, and site, of the infection. Natural killer (NK)-cell activation by most pathogens seems to occur indirectly, and is dependent on signals from accessory cells, such as monocytes, macrophages and dendritic cells. This Review examines how the interactions between NK cells, accessory cells and a diverse range of pathogens occur. Natural killer (NK) cells have a crucial role in combating infections and cancers and their surface receptors can directly recognize and respond to damaged, transformed or non-self cells. Whereas some virus-infected cells are recognized by this same route, NK-cell responses to many pathogens are triggered by a different mechanism. Activation of NK cells by these pathogens requires the presence of accessory cells such as monocytes, macrophages and dendritic cells. Recent studies have identified numerous pathogen-recognition receptors that enable accessory cells to recognize different pathogens and subsequently transmit signals — both soluble and contact-dependent — to NK cells, which respond by upregulating their cytotoxic potential and the production of inflammatory cytokines.