Effector Functions of NK Cells

The effector functions of NK cells are to kill infected cells and to activate macrophages to destroy phagocytosed microbes (Fig. 4-8). The mechanism of NK cell-mediated cytotoxicity is essentially the same as that of CD8+ CTLs, which we will describe in detail in Chapter 10. NK cells, like CTLs, have granules containing proteins that mediate killing of target cells. When NK cells are activated, granule exocytosis releases these proteins adjacent to the target cells. One NK cell granule protein, called perforin, facilitates the entry of other granule proteins, called gran-zymes, into the cytoplasm of target cells. The granzymes are enzymes that initiate a sequence of signaling events that cause death of the target cells by apoptosis. The signaling pathways that cause apoptosis are discussed in Chapter 14. By killing cells infected by viruses and intracellular bacteria, NK cells eliminate reservoirs of

Macrophage with phagocytosed microbes

FIGURE 4-8 Functions of NK cells. A, NK cells recognize ligands on infected cells or cells undergoing other types of stress and kill the host cells. In this way, NK cells eliminate reservoirs of infection as well as dysfunctional cells. B, NK cells respond to IL-12 produced by macrophages and secrete IFN-y, which activates the macrophages to kill phagocytosed microbes.

Macrophage with phagocytosed microbes

FIGURE 4-8 Functions of NK cells. A, NK cells recognize ligands on infected cells or cells undergoing other types of stress and kill the host cells. In this way, NK cells eliminate reservoirs of infection as well as dysfunctional cells. B, NK cells respond to IL-12 produced by macrophages and secrete IFN-y, which activates the macrophages to kill phagocytosed microbes.

infection. Some tumors, especially those of hematopoietic origin, are targets of NK cells, perhaps because the tumor cells do not express normal levels or types of class I MHC molecules.

NK cell-derived IFN-y serves to activate macrophages, like IFN-y produced by T cells, and increases the capacity of macrophages to kill phagocytosed bacteria (see Chapter 10). IFN-y produced by NK cells in lymph nodes can also direct the differentiation of naive T cells into TH1 cells (see Chapter 9).

NK cells play several important roles in defense against intracellular microbes. They kill virally infected cells before antigen-specific CTLs can become fully active, that is, during the first few days after viral infection. Early in the course of a viral infection, NK cells are expanded and activated by IL-12 and IL-15, and they kill infected cells, especially those that display reduced levels of class I MHC molecules. In addition, IFN-y secreted by NK cells activates macrophages to destroy phagocytosed microbes. This IFN-y-dependent NK cell-macrophage reaction can control an infection with intracellular bacteria such as Listeria monocytogenes for several days or weeks and thus allow time for T cell-mediated immunity to develop and eradicate the infection. Depletion of NK cells leads to increased susceptibility to infection by some viruses and intracellular bacteria. In mice lacking T cells, the NK cell response may be adequate to keep infection with such microbes in check for some time, but the animals eventually succumb in the absence of T cell-mediated immunity. NK cells may also be important later in the body's response to infection by killing infected cells that have escaped CTL-mediated immune attack by reducing expression of class I MHC molecules. Because NK cells can kill certain tumor cells in vitro, it has also been proposed that NK cells serve to kill malignant clones in vivo.

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