Immune Defense against Bacterial Pathogens: Adaptive or Acquired Immunity (page 6)
(This chapter has 6 pages)
© Kenneth Todar, PhD
Cell-mediated Immunity (CMI )is a type of resistance in which
cells of the immunological system
are directly involved, but antibody production or activity is of minor
importance. CMI differs from AMI in that immunity cannot be transferred
(passively) from animal to animal by antibodies or serum, but can be
by lymphocytes removed from the blood.
The CMI response
During the cell-mediated immune response, various subsets of T
are activated and develop into effector T cells. These include cytotoxic
T lymphocytes (CTLs or Tc cells) and T helper cells
of the TH1 and TH2
subsets. TH1 cells secrete
that activate macrophages and mediate delayed type hypersensitivity
TH2 cells secrete lymphokines that stimulate B
cell development and may
help activate Tc cells to their full cytotoxic capacity.
T cells that generate CMI are present in lymphoid organs, blood
and lymph nodes. Due to constant recirculation between blood and lymph
via lymphatics and back to the blood, one T-cell circulates once in
24 hours. Each carries receptors for the specific Ag with which it can
react. T-cell recognition of Ag only occurs when the Ag is associated
proteins of the MHC complex. T-cells have receptors (TCR)
to the complexed MHC determinant and the antigenic epitope. TH1
and TH2 cells recognize Ag in association with
MHC II (as displayed by
macrophages and other APCs); Tc cells recognize Ag on cells complexed
MHC I (as displayed by altered self cells).
Stepwise Activation of Tc cells
During a primary CMI response, antigen is presented to the precursor
Tc lymphocytes (CD8+) in association with MHC Class I
All nucleated cells express MHC I on their surfaces, so virtually any
in the animal expressing a new ("nonself") Ag on its surface will
the cytotoxic T lymphocytes. TH2 cells can
augment activation of Tc
cells, but they probably are not required.
Activation of TH
TH-cells (CD4+) reacting with Ag
may produce a variety of
lymphokines. Notably, Interleukin-2 (IL-2) stimulates T-cell activation
and IL-4 stimulates B cells.
composed of distinct subsets that are best distinguished on the basis
their patterns of lymphokine production. Both types of TH
cells develop under most conditions but their
and the predominance of certain lymphokines can vary, and this may
the pathology and outcome of certain bacterial infections.
TH1 cells "see" foreign Ag on the surface of
APCs in the context of
MHC II. Mainly, TH1 cells produce IL-2, gamma
interferon (IFN) and lymphotoxin. This
results in macrophage activation and the delayed-type hypersensitivity
reaction, as well as help for Tc cell activation.
TH2 cells also see foreign Ag on the surface
of APCs in the context
of MHC II. Their response is to secrete IL-4, IL-5, IL-6, IL-10 and
that help activate B cells, provide help for the production of IgE that
attaches to mast cells, and promote mast cell and eosinophil
The lymphokines produced by TH cells
stimulate B cells and pTc
inducing them to proliferate and mature into effector cells. Gamma
activates macrophages and Natural Killer (NK) cells to their full
potential. Lymphotoxins, such as tumor necrosis factor (TNF) cause
fever and kill cells
at a distance.
Function of cytotoxic T-lymphocytes
Tc cells (CTLs) can destroy cells bearing new antigens on their
surfaces (as might result in a viral infection, a tumor cell, or an
by a bacterial intracellular parasite). Tc cells exert their cytotoxic
activity when they are in physical contact with cells bearing new Ag in
MHC I protein. Contact between the Tc cell and the target cell is
for lysis, although the exact mechanism of lysis is not well
cell membrane is damaged at the site of contact (the "kiss of death")
a gaping hole about 40 nm in diameter that cannot be repaired. When the
Tc cell moves away 30-60 seconds later, there is leakage of the cell
an influx of H2O, and the target cell swells up and dies.
the Tc cell releases some of its cytolytic contents directly into the
cell, so that within a few minutes the target cell literally
The Tc cell can move away and kill again.
Tc cells generally respond to Ag in association with MHC I proteins
on the surface of a target cell. If they responded to Ag by itself,
could react with it when it was free in extracellular fluids, and their
cytotoxic activity would be triggered with no purpose. As stated
almost all host cells, including macrophages, display MHC I. Hence, an
effector Tc cell can destroy a macrophage which is otherwise carrying
a useful function by presenting Ag to TH
lymphocytes as part of the AMI
or CMI responses. Usually, the time course of the response is such that
TH cells have already developed and have carried
out their (helping)
when Tc cells begin to become active.
Delayed Type Hypersensitivity
TH1-cells (CD4+) are a subset of
Ag in association with Class II (and possibly Class I) MHC proteins.
When TH1-cells are presented Ag in association
with MHC II by a macrophage,
their development is stimulated by macrophage Interleukin-1 (IL-1), and
auto stimulated by IL-2, which the TH cell
produces. They respond by
and producing a variety lymphokines that induce a local inflammatory
and which attract, trap, and activate phagocytes at the site. One
aspect of this response
is a state of delayed-type hypersensitivity in the host.
is usually evident in chronic infections wherein CMI is largely
reactions usually present themselves
reactions. Such allergic reactions generally require about 24 hours
to develop following a secondary exposure to Ag. This time is required
for the circulating TH cells (actually memory
cells) to encounter the
and to produce cytokines that attract macrophages and Tc
to the site wherein an allergic
response is established.
The phagocytic and cytolytic activities of these cells are responsible
for the localized tissue destruction which occurs. Poison oak (ivy)
is a familiar example of delayed hypersensitivity, but the reaction is
also evident in several types of chronic or persistent bacterial
including tuberculosis, leprosy and brucellosis, and in some fungal and
One of the best known examples of the delayed-type hypersensitivity
reaction is the Mantoux (tuberculin) test which is utilized to
current or previous infection by the tubercle bacillus (Mycobacterium
tuberculosis). A small amount of Ag called the purified protein
(PPD), derived from the cell wall of the bacterium, is injected
subcutaneously under the skin of the forearm. The test is evaluated
24-48 hours. A positive test is an allergic response (an "urticarial
at the site of the injection, which might look like a swollen reddened
area about the size of a quarter. A negative test is no reaction. A
test does not mean that the individual has an active case of
but that the individual has at least been exposed to the tubercle
or one of its products sufficiently to have undergone a primary immune
Other types of cells other than dermal macrophages have been
as antigen presenting cells (APCs) to initiate DTH reactions on the
skin, including dendritic cells,
epidermal Langerhans cells and venular endothelial cells. In humans,
presentation by Langerhans cells (which bear class II MHC), probably
sensitization, whereas antigen presentation by endothelial cells
initiates DTH reactions upon secondary challenge.
5-hydroxytryptamine (5HT) has been shown to act as an adjuvant in
the induction of the
delayed-type hypersensitivity (DTH) response to purified protein
derivative (PPD). This supports the hypothesis that DTH reactions
mediated by macrophages and dendrocytes require a cascade of both
inflammatory and immunological signals.
Involvement of macrophages in mediation of
During induction of the cell-mediated immune response, macrophages
their usual role in the presentation of Ag to T helper cells and in
cytokines that are involved in the initiation of immune reactions. In
as in the case of DTH (above), macrophages play a role in the
expression of CMI. Many of the
produced by TH cells are aimed at attraction, entrapment and activation
of macrophages at the site of the reaction. One of these lymphokines, Gamma
Interferon, causes the local macrophage population to develop an
number of lysosomes and increased ability to secrete microbicidal
Oxygen-dependent killing mechanisms of the macrophage are stimulated,
the macrophage develops increased power to ingest and kill
Such lymphokine-stimulated macrophages are referred to as "angry" or
Compared to normal macrophages, activated macrophages
much greater ability to destroy intracellular pathogens. Activated
may play an important role in the recovery from chronic bacterial
and in resistance to certain tumors. Activated macrophages may be able
to overcome bacterial intracellular parasites which are able to thwart
the macrophage killing mechanisms before activation.
in CMI may be part of the pathology of certain diseases. Where there is
difficulty in elimination an intracellular parasite (e.g. the
bacillus) the chronic CMI response to local antigens leads to the
of densely-packed macrophages which release fibrinogenic factors and
the formation of granulation and fibrosis. The resulting structure,
a granuloma, actually represents an attempt by the host to
a persistent infection.
Other Aspects of cell-mediated immunity
Another class of cytotoxic lymphocytes distinct from Tc cells may be
stimulated during the cell-mediated immune response. These are referred
to as Natural Killer or NK cells. NK cells are found in
and lymphoid tissues, especially the spleen. They do not bear T cell
B cell) markers. Like Tc cells, they are able to recognize and kill
that are displaying a foreign Ag on their surfaces, but unlike Tc
do not display TCR and they are not MHC-restricted.
NK cells are present in an
in the absence of antigenic stimulation, and it is for this reason that
they are referred to as "natural" killers. They might also be
part of the innate immune defenses; however, NK cells become activated
a CMI response by T-cell lymphokines, including Interleukin-2 and gamma
Some NK cells are thought to be an immature form of a T-lymphocyte,
but various other types of cells including macrophages, neutrophils and
eosinophils, display NK activity. Some NK cells have surface receptors
(CD16) for the Fc portion of IgG. They bind to target cells by
for the Fc portion of antibody that has reacted with antigen on the
cell. This type of CMI is called antibody-dependent cell-mediated
or ADCC. NK cells may also have receptors for the C3b component
complement, and therefore recognize cells that are coated with C3b as
ADCC is thought to be an important defense against a variety of
infections caused by protozoa and helminths.
Summary: cells involved in expression of CMI
Cell mediated immunity (CMI) is carried out by several types of
including macrophages, TH lymphocytes Tc
lymphocytes, and NK
cells. After an immunological encounter, these cells are activated to
and/or respond to various classes of lymphokines that are the mediators
of CMI. A summary of the role of these cells in the expression of
is provided below.
Tc (cytotoxic) Lymphocytes (CTLs)
kill cells bearing foreign Ag on surface in association with MHC I. Tc
cells can kill cells that are harboring intracellular parasites (either
bacteria or viruses) as long as the infected cell is displaying a
antigen on its surface. Tc cells kill tumor cells and account for
of transplanted cells. Tc cells recognize Ag-MHC I complexes on target
cells, contact them, and release the contents of granules directly into
the target cell membrane which lyses the cell.
that are "helper" factors for development of B-cells into
plasma cells. They also produce certain lymphokines which stimulate the
of effector T lymphocytes and the activity of macrophages. TH1 cells
Ag on macrophages in association with MHC II and become activated (by
to produce lymphokines including gamma Interferon that activates
and NK cells. These cells mediate various aspects of the CMI response
delayed type hypersensitivity reactions. TH2
cells recognize Ag in
with MHC II on an APC and then produce interleukins and other
that stimulate specific B-cell and T-cell proliferation and activity.
Macrophages are an important as
cells (APCs) that initiate T-cell interactions, development and
Macrophages are also involved in expression of CMI since they become
by gamma IFN produced in a CMI response. Activated macrophages have
phagocytic potential and release soluble substances that cause
and destroy many bacteria and other cells.
Natural killer (NK) cells are
cells that lyse cells bearing new antigen regardless of their MHC type
and even lyse some cells that bear no MHC proteins. Natural Killer
are defined by their ability to kill cells displaying a foreign Ag
tumor cells) regardless of MHC type and regardless of previous
(exposure) to the Ag. Some NK cells are probably derived from Tc cells
(CTLs), but they do not display T cell markers. NK cells can be
by IL-2 and gamma IFN. Natural Killers lyse cells in the same manner as
CTLs. Some NK cells have receptors for the Fc domain of IgG and so are
able to bind to the Fc portion of IgG antibody on the surface of a
cell and release cytolytic components that kill the target cell. This
of killing is referred to as antibody-dependent cell-mediated
Summary: Lymphokines involved in expression
Extracellular factors that affect cell proliferation and
have been defined as cytokines. These include the lymphokines, which
proteins produced by T-lymphocytes that have effects on the
proliferation and activity of various cells involved in the expression
of CMI. In general, lymphokines function by (1) focusing circulating
and lymphocytes into the site of immunological encounter; (2)
the development and proliferation of B-cells and T-cells; (3)
and preparing macrophages for their phagocytic tasks; (4) stimulating
killer (NK) cells; (5) providing antiviral cover and activity. The
and functions of some of the important lymphokines are described below.
IL-1 (Interleukin-1): Initially
called lymphocyte activation factor. Mainly a product of macrophages,
has a variety of effects on various types of cells. It acts as a growth
regulator of T-cells and B-cells, and it induces other cells such as
to produce proteins relevant to host defense. IL-1 forms a chemotactic
gradient for neutrophils and serves as an endogenous pyrogen which
fever. Thus, IL-1 plays an important role in both the immunological
and in the inflammatory response.
IL-2 (Interleukin-2): stimulates
the proliferation of T-cells and activates NK (natural killer) cells.
IL-3 (Interleukin-3): regulates
the proliferation of stem cells and the differentiation of mast cells.
IL-4 (Interleukin-4): causes B
proliferation and enhanced antibody synthesis.
IL-6 (Interleukin-6): (same as
Interferon) has effects on B cell differentiation and on antibody
and on T cell activation, growth, and differentiation. Probably has a
role in the mediation of the inflammatory and immune responses
by infection or injury.
attractant for neutrophils.
IL-13 (Interleukin-13): shares
of the properties of IL-4, and is a potent regulator of inflammatory
(gamma IFN) is produced by T cells and may be considered a lymphokine.
It is sometimes called "immune interferon" (alpha-Interferon is
interferon"; beta-Interferon is "fibroblast interferon").
has several antiviral effects including inhibition of viral protein
in infected cells. It also activates macrophages and NK cells, and
IL-1, IL-2, and antibody production.
Lymphotoxins: (Tumor Necrosis Factor-Beta):
(TNF-beta is produced by T cells; TNF-alpha is produced by T cells, as
well as other types of cells.) TNF kills cells, including tumor cells
a distance). It is also a pyrogen.
Colony Stimulating Factor (CSF):
several, including GMCSF, cause phagocytic white cells of all types to
differentiate and divide.
Contrasting Roles of the AMI and CMI
in Host Defense
AMI and CMI responses are generated during almost all infections,
the relative magnitude and importance of each type of response shows
variation in different hosts and with different infectious agents.
In some types of infections antibody plays a major role in immunity
or recovery. For example, viruses producing systemic disease with a
stage (viruses free in the blood as they spread from infected to
cells), such as poliomyelitis or yellow fever, can be neutralized
by circulating antibody. Pathogenic bacteria that multiply outside of
(nearly all bacteria) at sites accessible to antibody can can be
stopped by the forces of AMI. Diseases caused by
bacterial toxins (e.g. diphtheria and tetanus) are controlled by
antibodies that neutralize toxins. Circulating antibodies (and perhaps
secretory IgA, as well) present in immune animals can prevent
In other types of infections CMI is of supreme importance in
These tend to be infections where the microbe grows or multiplies
Bacterial infections of this nature include tuberculosis, brucellosis
syphilis. Recovery is associated with development of a pronounced CMI
even though it is CMI that contributes to the pathology of the disease.
The clearest picture of the importance of CMI in recovery from
is seen in certain viral infections (e.g. herpes, pox viruses and
measles). Viruses are always intracellular parasites and may
rarely expose themselves to the extracellular forces of AMI. Antibodies
could neutralize free virus particles liberated from cells but often
little influence on infected cells. The best strategic defense against
virus-infected cells seems to be to kill the infected cell when the
may be in a replicative (noninfectious) form. Many viruses, as they
cause foreign (viral) antigens to appear on the infected cell surface.
These cells are recognized by the host's CMI defenses and they become
cells for cytolysis. The infected cell can be destroyed before virus is
The CMI response also plays a role in destruction of tumor cells and
in rejection of tissue transplants in animals. A major problem in
of tissues from one individual to another is rejection which is often
on CMI response to "foreign" cells (not a perfect match antigenically).
Since tumor cells contain specific antigens not seen on normal cells
also may be recognized as foreign and destroyed by the forces of CMI.
tumor cells develop on a regular basis in animals, it may be the forces
o CMI that eliminate them or hold them in check The increase in the
of many types of cancer (tumors) in humans with advancement of age may
be correlated with a decline in the peak efficiency of the immune
that begins about 25 years of age.
In summary, antibody-mediated immunity (AMI) is probably most useful
as an immune defense because of its ability to neutralize or destroy
pathogens and to prevent occurrence of reinfection. Cell-mediated
(CMI) plays the major role in immune defense against infections caused
by intracellular parasites, infections caused by viruses (either
or oncogenic), rejection of transplanted tissues or cells, and in the
of tumor cells. The contrasting roles of AMI and CMI as specific
immunological responses are presented in the following table.
Table 2. Relative
Importance of AMI
and CMI in Various Types of Infections
|Type of Infectious Agent
|MULTIPLIES INSIDE TISSUE CELLS
Kill infected cell
|AMI: IgG, IgA, IgM
CMI: Tc, NK, ADCC
|MULTIPLIES INSIDE PHAGOCYTES
||viruses, Mycobacterium tuberculosis
|Kill infected phagocytes
||CMI: Tc, NK, ADCC
|MULTIPLIES OUTSIDE CELLS
||Kill microbe extracellularly
||AMI: Complement- mediated lysis
|Opsonized phagocytosis and lysis
||AMI: IgG, IgM
||AMI: IgG, IgM
|MULTIPLIES OUTSIDE CELLS BUT ATTACHMENT TO
||streptococci E. coli Neisseria
END OF CHAPTER
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