NK cells are larger than T and B cells, have distinctive cytoplasmic granules containing cytotoxic proteins, and are functionally identified by their ability to kill certain tumor cell lines in vitro without the need for specific immunization. NK cells kill cells by releasing their cytotoxic granules, which are similar to those of cytotoxic T cells and have the same effects (discussed in Chapter 9). In brief, the contents of cytotoxic granules, which contain granzymes and the pore-forming protein perforin, are released onto the surface of the target cell, and penetrate the cell membrane and induce programmed cell death. However, unlike T cells, killing by NK cells is triggered by germline-encoded receptors that recognize molecules on the surface of infected or malignantly transformed cells. A second pathway used by NK cells to kill target cells involves the TNF family member known as TRAIL (tumor necrosis factor-related apoptosis-inducing ligand). NK cells express TRAIL on their cell surface. TRAIL interacts with two TNFR superfamily ‘death’ receptors, DR4 and DR5 (encoded by TNFSF10A and B), that are expressed by many types of cells. When NK cells recognize a target cell, TRAIL stimulates DR4 and DR5 to activate the pro-enzyme caspase 8, which leads to apoptosis. In contrast to pyroptosis, induced by caspase 1 following inflammasome activation (see Section 3-9), apoptosis is not associated with production of inflammatory cytokines. We will return to discuss more details of the mechanisms of caspase-induced apoptosis when we discuss killing by cytotoxic T cells in Chapter 9. Finally, NK cells express Fc receptors (see Section 1-20); binding of antibodies to these receptors activates NK cells to release their cytotoxic granules, a process known as antibody-dependent cellular cytotoxicity, or ADCC, to which we will return in Chapter 10.
The ability of NK cells to kill target cells can be enhanced by interferons or certain cytokines. NK cells that can kill sensitive targets can be isolated from uninfected individuals, but this activity is increased 20to 100-fold when NK cells are exposed to IFN-αand IFN-β, or to IL-12, a cytokine produced by dendritic cells and macrophages during infection by many types of pathogens. Activated 1 2 3 4 5 6 7 8 9 10 time after viral infection (days) NK-cell-mediated killing of infected cells T-cell-mediated killing of infected cells virus titer production of IFN-˜, IFN-°, TNF-˜, and IL-12
Fig. 3.38 Natural killer cells (NK cells) are an early component of the host response to virus infection. Experiments in mice have shown that IFN-α, IFN-β, and the cytokines TNF-α and IL-12 are produced first, followed by a wave of NK cells, which together control virus replication but do not eliminate the virus. Virus elimination is accomplished when virus-specific CD8 T cells and neutralizing antibodies are produced. Without NK cells, the levels of some viruses are much higher in the early days of the infection, and the infection can be lethal unless treated vigorously with antiviral compounds.
NK cells serve to contain virus infections while the adaptive immune response is generating antigen-specific cytotoxic T cells and neutralizing antibodies that can clear the infection (Fig. 3.38). A clue to the physiological function of NK cells in humans comes from rare patients deficient in these cells, who are frequently susceptible to herpesvirus infection. For example, a selective NK-cell deficiency results from mutations in the human MCM4 (minichromosome maintenance-deficient 4) protein, which is associated with predisposition to viral infections.