326
U N I T 4
Infection and Immunity
multifunctional
macrophage
. Phagocytes are activated
to engulf and digest microbes that attach to their cell
membrane. Once the cell is activated and the microbe
ingested, the cell generates digestive enzymes and toxic
oxygen and nitrogen intermediates (e.g., hydrogen
peroxide or nitric oxide) that kill the pathogen. The
phagocytic killing of microorganisms helps prevent the
spread of infectious agents until adaptive immunity
can be marshaled.
Dendritic cells
, which are derived from bone mar-
row cells and related in lineage to the macrophage, also
play important roles in the innate immune response to
infections and in linking innate and adaptive immune
responses (to be discussed in section on antigen-present-
ing cells). One subpopulation of dendritic cells governs
the early response to viral infections. They recognize
phagocytosed viruses and produce type 1 interferons
that have potent antiviral actions.
NK cells are a class of lymphocytes that recognize
infected and stressed cells and respond by killing these
cells. Activation of NK cells triggers the release of
cytoplasmic granules toward the infected cells. These
NK granules contain molecules that form pores in the
cell membrane and other molecules that induce apop-
tosis (programmed cell death). NK cells control their
responses by using both activating and inhibitory
receptors (Fig. 15-4). Their activating receptors (i.e.,
killer cell receptors) recognize altered host molecules
expressed on stressed tissue cells that may be infected
with intracellular microbes. The inhibitory receptors
on NK cells recognize molecules on normal host cells
and function to stop the killing response. This control
ensures that normal body cells are not inappropri-
ately destroyed. In contrast to the cytotoxic T lym-
phocytes of the adaptive immune system, which need
to undergo amplification and maturation to become
cytotoxic, the NK cell is directly programmed to kill
foreign cells.
Pathogen Recognition
The ability of leukocytes and epithelial cells to par-
ticipate in innate immunity depends on their first rec-
ognizing molecules that are a normal component of
microbes but not host cells. These components are
often essential for infectivity and cannot be mutated to
allow the microbe to evade destruction. The receptors
that the innate immune system uses to recognize and
react against microbes are expressed on phagocytic
leukocytes, NK cells, and other cells that participate
in defense against various classes of microbes. These
receptors are molecules that first tag the microbe and
then bind it to the effector cell of the innate immune
system. Microbial binding results in effector cell acti-
vation, phagocytosis, and subsequent killing of the
microbe. Several classes of receptors have been identi-
fied that are specific for different types of microbial
products including pattern receptors, Toll-like recep-
tors, and serum proteins (e.g., complement proteins)
that promote phagocytosis.
Pattern Recognition
Microbes typically bear repeating patterns of molecular
structure on their surface. The cell walls of Gram-negative
and Gram-positive bacteria are composed of a matrix of
sugars, lipid molecules, proteins, or patterns of modified
nucleic acids. The lipopolysaccharides of the outer wall
of Gram-negative bacteria, for example, are important
recognition sites for the innate immune system. Other
microbial components also have repetitive structures.
Bacterial DNA contains unmethylated cysteine-guanine
(CpG) sequences and viruses invariably express double-
stranded RNA as part of their life cycle. These repetitive
FIGURE 15-4.
Natural killer (NK) cell receptors.
(A)
NK cells
express activating receptors that respond to ligands from
virus-infected or injured cells and inhibiting receptors that bind
to the class I major histocompatibility complex (MHC-I) self-
recognition molecules expressed by normal cells. Normal cells
are not killed because inhibitory signals from normal MHC-I
molecules override activating signals.
(B)
In virus-infected
or tumor cells, increased expression of ligands for activating
receptors and reduced expression or alteration of MHC
molecules interrupts the inhibitory signals, allowing activation
of NK cells and lysis of target cells.
Normal cell
NK cell
Inhibitory receptor
MHC-I self-recognition
peptide
Activating receptor
Ligands for
activating receptor
No cell killing
A
Inhibitory receptor
not engaged
Virus inhibits
MHC-I expression
Cell killing
Virus-infected cell
B
