Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

1304 Chapter 24: The Innate and Adaptive Immune Systems
double-stranded RNA (dsRNA) that is an intermediate in the life cycle of many
viruses and is recognized by several PRRs including the Toll-like receptor TLR3;
in addition, DNA virus genomes frequently contain significant amounts of the
CpG motifs discussed earlier, which can be recognized by TLR9 (see Table 24–1,
p. 1300).
Mammalian cells are particularly adept at recognizing the presence of dsRNA,
which activates intracellular PRRs that induce the host cell to produce and secrete
two antiviral cytokines—interferon-α (IFNα) and interferon-β (IFNβ). These
interferons are referred to as type I interferons to distinguish them from IFNγ,
which is a type II interferon and has different functions, as we discuss later. Type
I interferons act in both an autocrine fashion on the infected cells that produced
it and a paracrine fashion on uninfected neighbors. They bind to a common
cell-surface receptor, which activates the JAK–STAT intracellular signaling pathway
(see Figure 15–56) to stimulate specific gene transcription and thereby the
production of more than 300 proteins, including many cytokines, reflecting the
complexity of the cell’s acute response to a viral infection.
The production of type I interferons appears to be a general response of mammalian
cells to a viral infection, and viral components other than dsRNA can trigger
it. The type I interferons help block viral replication in multiple ways. They
activate a latent ribonuclease that nonspecifically degrades single-stranded RNA.
They also indirectly activate a protein kinase that phosphorylates and inactivates
the protein synthesis initiation factor eIF2 (discussed in Chapter 6), thereby shutting
down most protein synthesis in the infected host cell. Apparently, by destroying
most of its own RNA and transiently halting most of its protein synthesis, the
host cell inhibits viral replication without killing itself. If these measures fail, the
cell takes an even more extreme step to prevent the virus from replicating: it kills
itself by undergoing apoptosis, often with the help of immune killer cells, as we
discuss next.
Natural Killer Cells Induce Virus-Infected Cells to Kill Themselves
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.
natural killer cell
cancer cell
5 µm
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 MBoC6 it induced m24.57/24.10 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.)