Chapter 13
Innate and Adaptive Immunity
299
which further enhances the phagocytic, metabolic, and
enzymatic functions of the cell-mediated immune response.
This results in a more rapid and more efficient destruction
of infected cells. This type of defense is important against
many intracellular pathogens such as
Mycobacterium
species
and
Listeria monocytogenes
but unfortunately plays a role in
delayed hypersensitivity reactions. Allergic contact dermatitis
(delayed hypersensitivity type IV) results from the activation
of both CD4
+
and CD8
+
T-cell precursors in the lymph nodes
draining the site of antigen presentation. These “haptenated
peptides” stimulate the recruitment of T cells at the site of anti-
gen presentation, inducing inflammatory signals and apoptosis
of epidermal cells, leading to the development of inflammation,
to the release of chemical mediators, and to clinical symptoms.
In cell-mediated immune responses, the actions of
T lymphocytes and effector macrophages predominate. The
most aggressive and abundant phagocyte, the macrophage,
becomes activated after exposure to T-cell cytokines, espe-
cially IFN-
γ
.
23
The initial stages of cell-mediated immunity
are initiated when an APC displays an antigen peptide–class
I or II MHC complex to the CD4
+
helper T cell and activates
it. The activated helper T cell then synthesizes IL-2, IL-4,
and other cytokines, which stimulate increased production of
CD4
+
helper T cells and then amplify the response. Additional
cytokine release enhances the activity of cytotoxic T cells and
effector macrophages.
Regulatory T Cells
Regulatory T cells (T
R
) are a subset of T lymphocytes that
function to control immune system responses. Different popu-
lations of T
R
cells produced in the thymus have been identified
including those that express CD4 and CD25 on their surface.
These cells represent a subset of CD4
+
cells that act as “neg-
ative regulators” of the immune process
34
. They suppress
immune responses by inhibiting the proliferation of other
potentially harmful self-reactive lymphocytes. Production of
regulatoryTcells is highlydependent upon thepresenceof anti-
gen, activation of a TCR by the antigen, and the release of the
cytokines IL-10 and transforming growth factor-
β
(TGF-
β
).
34
These cytokines inhibit the proliferation and activation of
lymphocytes and macrophages. There is also recent evidence
of the existence of regulatory CD8
+
T cells that can selec-
tively down-regulate T cells activated by either self or foreign
antigens. These cells differentiate into regulatory cells during
the primary immune response and function to suppress the
secondary immune response. The CD8
+
regulators are, there-
fore, primarily involved in self–nonself discrimination. The
ability of the regulatory T cells to control many aspects of
the immune response has significant implications for clinical
practice. Promise has been shown in the control of inflam-
matory bowel disease, experimental allergic encephalitis, and
autoimmune diabetes.
Cytotoxic T Cells
The primary function of cytotoxic T (CD8
+
) cells is to monitor
the activity of all cells in the body and destroy any that threaten
the integrity of the body. CD8
+
T cells recognize antigens that
are presented on the cell surface by MHC class I–derived
molecules that sample peptides from protein degradation pro-
ductions from inside cells infected by viruses or transformed
by cancer
33
(Fig. 13.11). The ability of CD8
+
cells to recog-
nize the class I MHC–antigen complexes on infected target
cells ensures that neighboring uninfected host cells, which
express class I MHC molecules alone or with self-peptide,
are not indiscriminately destroyed. The CD8
+
cytotoxic
T lymphocytes destroy target cells by a variety of mechanisms
including the release of cytolytic enzymes, toxic cytokines,
and pore-forming molecules (
i.e.,
perforins) or by triggering
membrane molecules and intracellular apoptosis. Apoptosis is
a normal biological process that eliminates excessive, danger-
ous, or damaged cells from the body. The CD8
+
T cells play
a large role in controlling replicating viruses and intracellular
bacteria because antibody cannot readily penetrate the mem-
brane of living cells.
Cell-Mediated Immunity
In order for the cell-mediated immune response to carry out its
function, healthy CD4
+
and CD8
+
T lymphocytes are required.
Activated CD4
+
helper T cells release various cytokines (
i.e.,
IFN-
γ
) that recruit and activate other CD8
+
cytotoxic T cells,
macrophages, and inflammatory cells. Cytokines (
e.g.,
che-
mokines) stimulate migration of several types of inflamma-
tory cells, including macrophages, neutrophils, and basophils,
IL-2
receptor
Antigen
TCR
CD8
MHC-I
CD4
TCR (already triggered)
Activated
helper
T cell
Cytotoxic
T cell
Target
cell
(cell death)
Cytokines
Perforins
Toxic cytokines
IL-2
FIGURE 13.11
•
Destruction of target cell by cytotoxic T cell.
Cytokines released from the activated helper T cell enhance the potential
of the cytotoxic T cell in destruction of the target cell.
