attached helper T cell to provide yet another important stimu-
lus for activation.
Thus, the APC participates in the activation of a helper
T cell in three ways: (1) antigen presentation, (2) provision of
a costimulus in the form of a matching nonantigenic plasma
membrane protein, and (3) secretion of IL-1, TNF, and other
cytokines (see Figure 18–12).
The activated helper T cell itself now secretes various
cytokines that have both autocrine effects on the helper T cell
and paracrine effects on adjacent B cells and any nearby cyto-
toxic T cells, NK cells, and still other cell types. These pro-
cesses will be described in later sections.
Presentation to Cytotoxic T Cells
Because class I MHC proteins are synthesized by virtually all
nucleated cells, any such cell can act as an APC for a cytotoxic
T cell. This distinction helps explain the major function of
cytotoxic T cells—destruction of
of the body’s own cells
that have become cancerous or infected with viruses. The key
point is that the antigens that complex with class I MHC pro-
body cells. They are endogenous antigens,
synthesized by a body cell.
How do such antigens arise? In the case of viruses, once
a virus has taken up residence inside a host cell, the viral nucleic
acid causes the host cell to manufacture viral proteins that are
foreign to the cell. A cancerous cell has had one or more of
its genes altered by chemicals, radiation, or other factors. The
altered genes, called
code for proteins that are not
normally found in the body. Such proteins act as antigens.
In both virus-infected cells and cancerous cells, some of
the endogenously produced antigenic proteins are hydrolyzed
by cytosolic enzymes (in proteasomes) into peptide fragments,
which are transported into the endoplasmic reticulum. There
they are complexed with the host cell’s class I MHC proteins
and then shuttled by exocytosis to the plasma membrane sur-
face, where a cytotoxic T cell speciﬁ c for the complex can bind
to it (
As noted earlier, NK (natural killer) cells constitute a distinct
class of lymphocytes. They have several functional similarities
to those of cytotoxic T cells. For example, their major targets
are virus-infected cells and cancer cells, and they attack and
kill these target cells directly, after binding to them. However,
unlike cytotoxic T cells, NK cells are not antigen speciﬁ c; that
is, each NK cell can attack virus-infected cells or cancer cells
without recognizing a speciﬁ c antigen. They have neither T-cell
receptors nor the immunoglobulin receptors of B cells, and
the exact nature of the NK-cell surface receptors that permits
the cells to identify their targets is unknown (except in one
case presented later). MHC proteins are not involved in the
activation of NK cells.
Why, then, do we deal with them in the context of
immune responses? Because, as will be described subse-
quently, their participation in an immune response is greatly
secreted by helper T cells activated during speciﬁ c immune
Development of Immune Tolerance
Our basic framework for understanding speciﬁ c immune
responses requires consideration of one more crucial ques-
tion: How does the body develop what is called
—lack of immune responsiveness to self? This may
seem a strange question given the deﬁ
nition of an antigen as a
foreign molecule that can generate an immune response. How
is it, though, that the body “knows” that its own molecules,
particularly proteins, are not foreign but are self molecules?
Recall that the huge diversity of lymphocyte receptors
is ultimately the result of multiple random DNA cutting/
recombination processes. It is virtually certain, therefore, that
in each person, clones of lymphocytes would have emerged
with receptors that could bind to that person’s own proteins.
The existence and functioning of such lymphocytes would be
disastrous because such binding would launch an immune
attack against the cells expressing these proteins. There are at
least two mechanisms, called
that explain why normally there are no active lympho-
cytes that respond to self components.
First, during fetal and early postnatal life, T cells are
exposed to a wide mix of self proteins in the thymus. Those
T cells with receptors capable of binding self proteins are
destroyed by apoptosis (programmed cell death). This process
The second process,
occurs not in the thymus but in the periphery and causes
potentially self-reacting T cells to become nonresponsive.
Class I MHC
Class I MHC
Cytotoxic T cell
Processing and presentation of viral antigen to a cytotoxic T cell by an
infected cell. Begin this ﬁ gure with the viral DNA in the cell’s nucleus.
The viral DNA induces the infected cell to produce viral protein, which
is then hydrolyzed (by proteasomes). The fragments are complexed to
the cell’s class I MHC proteins in the endoplasmic reticulum, and these
complexes are then shuttled to the plasma membrane.
Adapted from Gray, Sette, and Buus.