IL-12, acting in synergy with the cytokine IL-18 produced by activated macrophages, can also stimulate NK cells to secrete large amounts of interferon (IFN)-γ, and this is crucial in controlling some infections before the IFN-γ produced by activated CD8 cytotoxic T cells becomes available. IFN-γ, whose receptor activates only the STAT1 transcription factor, is quite distinct functionally from the antiviral type I interferons IFN-α and IFN-β, and is not directly induced by viral infection. The production of IFN-γ by NK cells early in an immune response can directly activate macrophages to enhance their capacity to kill pathogens, augmenting innate immunity, but also influences adaptive immunity through actions on dendritic cells and in regulating the differentiation of CD4 T cells into the pro-inflammatory TH1 subset, which produces IFN-γ. NK cells also produce TNF-α, granulocyte-macrophage stimulating factor (GM-CSF), and the chemokines CCL3 (MIF 1-α), CCL4, and CCL5 (RANTES), which act to recruit and activate macrophages.
3-25 NK cells express activating and inhibitory receptors to distinguish between healthy and infected cells.
For NK cells to defend against viruses or other pathogens, they should be able to distinguish infected cells from uninfected healthy cells. However, the mechanism used by NK cells is slightly more complicated than pathogen recognition by T or B cells. In general, it is thought that an individual NK cell expresses various combinations of germline-encoded activating receptors and inhibitory receptors. While the exact details are not clear in every case, it is thought that the overall balance of signaling by these receptors determines whether an NK cell engages and kills a target cell. The receptors on an NK cell are tuned to detect changes in expression of various surface proteins on a target cell, referred to as ‘dysregulated self.’ The activating receptors generally recognize cell-surface proteins that are induced on target cells by metabolic stress, such as malignant transformation or microbial infection. These changes are referred to as ‘stress-induced self.’ Specific cellular events, including DNA damage, signals related to proliferation, heat-shock related stress, and signaling by innate sensors including TLRs can lead to expression by host cells of surface proteins that bind to the activating receptors on NK cells. Stimulation of activating receptors will add to the chance that the NK cells will release cytokines such as IFN-γ and activate the killing of the stimulating cell through the release of cytotoxic granules.
By contrast, inhibitory receptors on NK cells recognize surface molecules that are constitutively expressed at high levels by most cells, and the loss of these molecules is referred to as ‘missing self.’ Inhibitory receptors can recognize other molecules, but those recognizing MHC class I molecules have been studied the most so far. MHC molecules are glycoproteins expressed on nearly all cells of the body. We will discuss the role of MHC proteins in antigen presentation to T cells in Chapter 6, but for now we need only to introduce the two main classes of MHC molecules. MHC class I molecules are expressed on most of the cells of the body (except, notably, red blood cells), whereas the expression of MHC class II molecules is far more restricted, largely to immune cells.