and then process and present antigen, in association with class
II MHC proteins, to the helper T cells. In addition, the mac-
rophages provide a costimulus and also secrete IL-1 and TNF.
The activated helper T cell releases IL-2 and other cytokines.
IL-2 then acts as an autocrine agent to stimulate proliferation
of the helper T cell.
The IL-2 also acts as a paracrine agent on the cytotoxic
T cell bound to the surface of the virus-infected or cancer
cell, stimulating this attack cell to proliferate. Other cyto-
kines secreted by the activated helper T cell perform the same
functions. Why is proliferation important if a cytotoxic T cell
has already found and bound to its target? The answer is that
there is rarely just one virus-infected cell or one cancer cell. By
expanding the clone of cytotoxic T cells capable of recogniz-
ing the particular antigen, proliferating attack cells increase
the likelihood that the other virus-infected or cancer cells will
be encountered by the speciﬁ c type of cytotoxic T cell.
There are several mechanisms of target cell killing by
activated cytotoxic T cells, but one of the most important is as
follows (see Figure 18–18): The cytotoxic T cell releases, by exo-
cytosis, the contents of its secretory vesicles into the extracellu-
lar space between itself and the target cell to which it is bound.
These vesicles contain a protein,
(also called pore-
forming protein), which is similar in structure to the proteins
of the complement system’s membrane attack complex. Perforin
inserts into the target cell’s membrane and forms channels
through the membrane. In this manner, it causes the attacked
cell to become leaky and die. The fact that perforin is released
directly into the space between the tightly attached cytotoxic
T cell and the target ensures that innocent host bystander cells
will not be killed because perforin is not at all speciﬁ c.
Some cytotoxic T cells generated during proliferation
following an initial antigenic stimulation do not complete their
full activation at this time but remain as memory cells. Thus,
active immunity exists for cytotoxic T cells just as for B cells.
Role of NK Cells and Activated Macrophages
Although cytotoxic T cells are very important attack cells
against virus-infected and cancer cells, they are not the only
ones. NK cells and activated macrophages also destroy such
cells by secreting toxic chemicals.
In the section on antibody-dependent cellular cytotoxic-
ity (ADCC), we pointed out that NK cells can be linked to
target cells by antibodies, and this certainly constitutes one
potential method of bringing them into play against virus-
infected or cancer cells. In most cases, however, strong anti-
body responses are not triggered by virus-infected or cancer
cells, and the NK cell must bind
to its target, without
the help of antibodies. As noted earlier, NK cells do not have
antigen speciﬁ city; rather, they nonspeciﬁ cally bind to any
virus-infected and cancer cell.
The major signals for NK cells to proliferate and secrete
their toxic chemicals are IL-2 and a member of the interferon
—secreted by the helper T cells
that have been activated speciﬁ cally by the targets (
). (Whereas essentially all body cells can produce the
other interferons, as described earlier, only activated helper T
cells and NK cells can produce interferon-gamma.)
Thus, the attack by the NK cells is nonspeciﬁ c, but a spe-
ciﬁ c immune response on the part of the helper T cells is required
to bring the NK cells into play. Moreover, there is a positive
feedback mechanism at work here because activated NK cells can
themselves secrete interferon-gamma (see Figure 18–19).
IL-2 and interferon-gamma act not only on NK cells but
on macrophages in the vicinity to enhance their ability to kill
cancer cells and cells infected with viruses and other microbes.
Macrophages stimulated by IL-2 and interferon-gamma are
(see Figure 18–19). They
secrete large amounts of many chemicals that are capable of
killing cells by a variety of mechanisms.
summarizes the multiple defenses against
viruses described in this chapter.
Systemic Manifestations of Infection
There are many
responses to infection—that is,
responses of organs and tissues distant from the site of infec-
tion or immune response. These systemic responses are collec-
tively known as the
acute phase response
is natural to think of them as part of the disease, but the fact is
Destroy target cells
helper T cell
IL-2 and interferon-gamma
Role of IL-2 and interferon-gamma, secreted by activated helper
T cells, in stimulating the killing ability of NK cells and macrophages.