Type I interferons also have less direct ways of blocking viral replication. One of these is to enhance the activity of natural killer cells (NK cells), which are leukocytes related to T and B cells but are part of the innate immune system and are recruited early to sites of inflammation. Like cytotoxic T cells of the adaptive immune system (discussed later), NK cells destroy virus-infected cells by inducing the infected cells to kill themselves by undergoing apoptosis (discussed in Chapter 18). We consider how killer cells induce apoptosis later, when we discuss how cytotoxic T cells do it (see Figure 24–43). Although they kill in the same way, the means by which cytotoxic T cells and NK cells distinguish the surface of virus-infected cells from that of uninfected cells are different (Movie 24.2).
Both cytotoxic T cells and NK cells recognize the same special class of cell-surface proteins on a host cell to help determine if the cell is virus-infected, but they use distinct receptors to do so. The special cell-surface proteins recognized are called class I MHC proteins, because they are encoded by genes in the major histocompatibility complex; almost all nucleated cells in vertebrates express these genes, and we discuss them in detail later. Cytotoxic T cells use both T cell receptors (TCRs) and co‑receptors to recognize peptide fragments of viral proteins bound to class I MHC proteins on the surface of virus-infected host cells and then induce the infected cells to kill themselves. By contrast, NK cells have cell-surface inhibitory receptors that monitor the level of class I MHC proteins on the surface of other host cells: the high levels of these MHC proteins normally present on healthy cells engage these receptors and thereby inhibit the killing activity of the NK cells. The NK cells thus focus primarily on host cells expressing abnormally low levels of class I MHC proteins and induce them to kill themselves; these are mainly virus-infected cells and some cancer cells (Figure 24–9). NK cell killing activity is stimulated when various activating receptors on the NK cell surface recognize specific proteins that are greatly increased on the surface of virus-infected cells and some cancer cells.
Figure 24–9 A natural killer (NK) cell attacking a cancer cell. This scanning electron micrograph was taken shortly after the NK cell attached to the cancer cell, but before it induced the cell to die by apoptosis. (courtesy of J.c. hiserodt, in Mechanisms of cytotoxicity by Natural Killer cells [r.B. herberman and D. callewaert, eds.]. New York: Academic press, 1995.)
The reason that class I MHC protein levels are often low on virus-infected cells is that many viruses have developed a variety of mechanisms to inhibit the expression of these proteins on the surface of the host cells they infect, in order to avoid detection by cytotoxic T cells: some viruses encode proteins that block class I MHC gene transcription; others block the intracellular assembly of pep-tide–MHC complexes; still others block the transport of these complexes to the cell surface. By evading recognition by cytotoxic T cells in these ways, however, a virus incurs the wrath of NK cells, which recognize the infected cells as being different—both because the infected cells express little class I MHC protein and because they express large amounts of other surface proteins that are recognized by the activating receptors on the NK cells (Figure 24–10).
Dendritic cells provide the Link Between the Innate and  Adaptive Immune Systems