IMMUNOLOGY AND IMMUNOCHEMISTRY MCB 301

DEPARTMENT OF BIOLOGICAL SCIENCES

FACULTY OF SCIENCE
BORNO STATE UNIVERSITY

MCB 301

IMMUNOLOGY AND IMMUNOCHEMISTRY

LECTURE NOTE

MUSTAFA ALHAJI ISA PhD.

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Immune System
From a microorganism’s standpoint, the tissues and fluids of the human body are much like a warm
culture flask filled with a nutrient-rich solution. Considering this, it may be surprising that the
interior of the body—including blood, muscles, bones, and organs—is generally sterile. If this
were not the case, microbes would simply degrade our tissues, just as they readily decompose the
carcasses of dead animals.
How does the interior of the body remain sterile in this world full of microbes? Like other
multicellular organisms, humans have evolved several mechanisms of defense. First, we are
covered with skin and mucous membranes that prevent entry of most foreign material, including
microbes, into the body. Ready in case the barriers are breached are sensor systems that detect
molecules associated with microbes. The sensors can direct and assist other host defenses,
facilitating the destruction of the invaders. Also lying in wait are defense cells that specialize in
ingesting and digesting microbes and other foreign material; if needed, additional reinforcements
can be recruited to the site of breach. The protection provided by these systems is termed innate
immunity.
Innate immunity had been called a non-specific defense, but recent discoveries have shown that
most of the components rely on the detection of certain molecules associated with invading
microbes, a feature called pattern recognition. The molecules recognized include various
compounds in bacterial cell walls (such as lipopolysaccharide, lipoteichoic acid, and
peptidoglycan) and other features unique to microbes.

Overview of the Innate Defenses

First-line defenses are the barriers that separate and shield the interior of the body from the
surrounding environment; they are the initial obstacles microorganisms must overcome to invade
the tissues. The anatomical barriers, which include the skin and mucous membranes, not only
provide physical separation, but are often bathed in secretions that have antimicrobial properties.
Sensor systems within the body recognize when the first-line barriers have been breached and then
relay that information to other components of the host defenses. Two important groups of sensors
are the toll-like receptors and NOD (nucleotide-binding oligomerization domain) proteins,
which are found on or within a variety of different cell types. These receptors recognize families
of compounds unique to microbes, enabling the cell to sense invaders and then send chemical
signals to alert other components of the host’s defense. Another type of sensor is a series of proteins
always present in blood and tissue fluids; these proteins are collectively called the complement
system because they can “complement,” or act in conjunction with, the adaptive immune defenses.
In response to certain stimuli, the complement proteins become activated, setting off a chain of
events that results in removal and destruction of invading microbes.
Phagocytes, cells that specialize in engulfing and digesting microbes and cell debris, act as
sentries, alert for signs of invasion of the body. More can be recruited from the bloodstream,
serving as reinforcements at the sites in tissues where first-line defences have been breached.

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Cells of the immune system communicate with one another by producing proteins that function as
chemical messengers, called cytokines. A cytokine produced by one cell diffuses to another and
binds to the appropriate cytokine receptor of that cell. When a cytokine binds a receptor, a signal
is transmitted to the interior of the cell, inducing certain changes in the activities of the cell. Some
types of cytokines endow cells with enhanced powers; others prompt cells to migrate to specific
locations within the body. When invading microorganisms or tissue damage is detected,
inflammation ensues; this is a coordinated response involving many aspects of the innate
defenses. During inflammation, the cells that line local blood vessels near the area of invasion or
damage undergo changes that allow proteins such as those of the complement system to leak into
tissues. Other changes allow phagocytic cells in the blood to adhere to the vessels and then squeeze
between cells, exiting the bloodstream. Phagocytic cells then migrate to the area of infection or
damage where they ingest and destroy foreign material. Some types of phagocytes play a dual role,
destroying invaders while also communicating with cells of the adaptive immune system, enlisting
their far more powerful effects.
Fever is another of the body’s innate defense mechanisms. This increase in internal body
temperature acts in several ways to discourage infection.
First-Line Defenses
The body’s first line of defense against invading microbes includes physical barriers such as the
skin and mucous membranes, and the antimicrobial substances in secretions that bathe those
barriers. Some of these barriers are often considered to be “inside” the body, but actually they are
in direct contact with external environment. For example, the digestive tract, which begins at the
mouth and ends at the anus, is simply a hollow tube that runs through the body, allowing intestinal
cells to absorb nutrients from food that passes through; the respiratory tract is a cavity that allows
O2 and CO2 to be exchanged. In addition to the protection provided by the anatomical barriers, the
normal microbiota—the population of microbes that routinely inhabit the body surfaces—helps
prevent harmful microbes from colonizing the body surfaces.
Physical Barriers
All exposed surfaces of the body are lined with epithelial cells. These cells are tightly packed
together and rest on a thin layer of fibrous material, the basement membrane.
Skin
The skin is the most obvious visible barrier and is the most difficult for microbes to penetrate. It
is composed of two main layers—the dermis and the epidermis. The dermis contains tightly woven
fibrous connective tissue, making it extremely tough and durable (the dermis of cattle is used to
make leather). The epidermis is composed of many layers of epithelial cells that become
progressively flattened toward the exterior. The outermost sheets are made up of dead cells
embedded with a water-repelling protein called keratin, resulting in the skin being an arid
environment. The cells continually slough off, taking with them any microbes that might be
adhering.
Mucous Membranes

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Mucous membranes line the digestive tract, respiratory tract, and genitourinary tract. They are
constantly bathed with mucus or other secretions that help wash microbes from the surface. Some
mucous membranes have mechanisms that propel microbes, directing them toward areas where
they can be eliminated more easily. For example, flow of urine regularly flushes organisms from
the urinary tract. Peristalsis, the rhythmic contractions of the intestinal tract, propels food and
liquid and also helps to expel microbes. The respiratory tract is lined with ciliated cells; the hairlike
cilia constantly beat in an upward motion, propelling materials away from the lungs to the throat
where they can then be swallowed. This “free ride” out of the respiratory tract is referred to as the
mucociliary escalator.
Antimicrobial Substances
Both the skin and mucous membranes are protected by a variety of antimicrobial substances that
inhibit or kill microorganisms. Sweat, for example, is high in salt; as it evaporates it leaves a salty
residue, inhibiting many organisms that might otherwise proliferate on the skin.
Lysozyme, the enzyme that degrades peptidoglycan, is found in tears, saliva, and in mucus that
bathes mucous membranes. It is also found within the body, in phagocytic cells, blood, and the
fluid that bathes tissues.
Peroxidase enzymes are found in saliva and milk; they are also found within body tissues and
inside phagocytes. These enzymes break down hydrogen peroxide and, in the process, produce
potent oxidizing compounds. Bacteria that produce the enzyme catalase, however, may avoid the
damaging products associated with peroxidase activity; catalase breaks down hydrogen peroxide,
potentially destroying the compound before it can interact with peroxidase. Catalase-negative
organisms are more sensitive to peroxidase killing.
Lactoferrin is an iron-binding protein found in saliva, mucus, and milk; it is also found in some
types of phagocytic cells. A similar compound, transferrin is found in blood and tissue fluids.
Iron, an important part of some enzymes, is one of the major elements required for growth. By
sequestering iron, the lactoferrin and transferrin effectively withhold the essential element from
most microbes. Some bacteria, however, make compounds that capture iron from the host, thus
circumventing this defense.
Defensins are short antimicrobial peptides produced by neutrophils and epithelial cells. They
function by inserting into bacterial membranes, forming pores that disrupt the integrity of the cell.
Normal Microbiota (Flora)
The population of microorganisms routinely found growing on the body surfaces of healthy
individuals is called the normal microbiota (flora). Although these organisms are not technically
part of the immune system, the protection they provide is considerable.
One protective effect of the normal microbiota is competitive exclusion of pathogens. For example,
the normal microbiota prevents invading organisms from adhering to host cells by covering
binding sites that might otherwise be used for attachment. The population also consumes available
nutrients that could otherwise be used by less desirable organisms. Members of the normal
microbiota also produce compounds toxic to other bacteria. In the hair follicles of the skin, for
example, Propionibacterium species degrade the lipids found in skin glands, releasing fatty acids

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that inhibit the growth of many pathogens. In the gastrointestinal tract, some strains of E. coli
synthesize colicins, proteins toxic to other strains of bacteria. Lactobacillus species growing in the
vagina produce lactic acid as a fermentation end product, resulting in an acidic pH that inhibits the
growth of some potential disease-causing organisms. Disruption of the normal microbiota, which
occurs when antibiotics are used, can predispose a person to various infections. Examples include
antibiotic-associated diarrhea, caused by the growth of toxin producing strains of Clostridium
difficile in the intestine, and vulvovaginitis, caused by excessive growth of Candida albicans in
the vagina
The Cells of the Immune System
The cells of the immune system can move from one part of the body to another, traveling through
the body’s circulatory systems like vehicles on an extensive interstate highway system. They are
always found in normal blood, but their numbers usually increase during infections, recruited from
reserves of immature cells that develop in the bone marrow. Some cells play dual functions, having
crucial roles in both innate and adaptive immunity. The formation and development of blood cells
is called hematopoiesis (Greek for “blood” and “to make”). All blood cells, including those
important in the body’s defenses, originate from the same type of cell, the hematopoietic stem
cell, found in the bone marrow. These stem cells are induced to develop into the various types of
blood cells by a group of cytokines called colony-stimulating factors. Some of the cells of the
immune system are already mature as they circulate in the bloodstream, but others differentiate,
developing functional properties, after they leave the blood and enter the tissues. The general
categories of blood cells and their derivatives include red blood cells, platelets, and white blood
cells. Red blood cells, or erythrocytes, carry oxygen in the blood. Platelets, which are actually
fragments arising from large cells called megakaryocytes, are important for blood clotting. White
blood cells, or leukocytes, are important in all host defenses. Leukocytes can be divided into four
broad groups—granulocytes, mononuclear phagocytes, dendritic cells, and lymphocytes.
Granulocytes
All granulocytes contain prominent cytoplasmic granules filled with biologically active
chemicals. There are three types of granulocytes—neutrophils, basophils, and eosinophils; their
names reflect the staining properties of their cytoplasmic granules.
Neutrophils are highly efficient at phagocytizing and destroying foreign material, particularly
bacteria, and damaged cells. The contents of their granules, which stain poorly, include many
antimicrobial substances and degradative enzymes essential for destruction of materials that the
cells engulf. They are the most abundant and important granulocytes of the innate responses.
Neutrophils are sometimes called polymorphonuclear neutrophilic leukocytes, polys, or PMNs,
names that reflect the appearance of multiple lobes of their single nucleus. They normally account
for over 50% of circulating leukocytes, and their numbers increase during most acute bacterial
infections. There are generally few in tissues except during inflammation. Because of the
importance of neutrophils in innate immunity, they will be described in more detail later in the
chapter.

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Basophils are blood cells involved in allergic reactions and inflammation. Their granules, which
stain dark purplish-blue with the basic dye methylene blue, contain histamine and other chemicals
that increase capillary permeability during inflammation.
Mast cells are similar in appearance and function to basophils but are found in virtually all tissues,
rather than in blood. They do not come from the same precursor cells as basophils. Mast cells are
important in the inflammatory response and are responsible for many allergic reactions.
Eosinophils are thought to be primarily important in expelling parasitic worms from the body.
They seem to be involved in allergic reactions, causing some of the symptoms associated with
allergies, but reducing others. The granules of eosinophils, which stain red with the acidic dye
eosin, contain antimicrobial substances and also histaminase, an enzyme that breaks down
histamine.
Mononuclear Phagocytes
Mononuclear phagocytes constitute a widespread collection of important phagocytic cells called
the mononuclear phagocyte system (MPS) (figure 1). They include monocytes, which circulate
in the blood, and the cell types that develop from monocytes as they leave the bloodstream and
migrate into tissues. Macrophages, a differentiated form of monocytes, are phagocytic cells
present in virtually all tissues to at least some extent. They are particularly abundant in liver,
spleen, lymph nodes, lungs, and the peritoneal (abdominal) cavity. Unfortunately for the novice,
however, they are given various different names based on the tissue in which they are found

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FIGURE 1: Blood Cells and their Derivatives

Dendritic Cells
Dendritic cells are found in various tissues throughout the body, where they function as “scouts.”
They routinely engulf material in the tissues, and then bring it to the cells of the adaptive immune
system for “inspection.” Dendritic cells develop from monocytes, but some also appear to descend
from other cell types.

Complement System
The complement system is a series of proteins that constantly circulate in the blood and the fluid
that bathes the tissues. Early studies showed that these proteins augment the activities of the
adaptive immune response; in fact, their name is derived from observations that they
“complement” the activities of antibodies. They routinely circulate in an inactive form, but in
response to certain stimuli indicating the presence of foreign material, a cascade of reactions
occurs. This results in the rapid activation of critical complement system components. These
activated forms have specialized functions that cooperate with other host defenses to quickly
remove and destroy the offending material.
Three pathways lead to the activation of the complement System

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1. Alternative pathway: The name of this pathway may seem to imply that it is “second
choice,” but it actually reflects the fact that it was not discovered first. In fact, the pathway
is quickly and easily initiated, providing vital early warning that an invader is present. The
alternative pathway relies on the binding of the complement protein C3b to cell surfaces,
allowing other complement proteins to subsequently attach and form a complement
activating complex. C3b is always present in blood and tissues to at least some extent, so
nearly any cell surface can trigger the pathway. The body’s own cells, prevent their surfaces
from activating the complement system by binding regulatory proteins that inactivate
bound C3b before the other complement proteins can attach.
2. Lectin pathway: Activation of the lectin pathway requires mannan-binding lectins
(MBLs); these are pattern-recognition molecules the body uses to detect mannan, a
polymer of mannose often found on microbial but rarely on mammalian cells. When MBL
attaches to a surface, it can then interact with one of the complement components,
activating it. This, in turn, leads to activation of other complement proteins.
3. Classical pathway: Activation by the classical pathway requires antibodies, a component
of adaptive immunity. When antibodies bind to antigen, they can then interact with the
same complement component involved in activating the lectin pathway. This activates that
protein, leading to activation of other complement proteins.
The nature of the complement system allows an exceedingly rapid and powerful response. Its
activation occurs by a cascade of reactions; once a specific complement protein becomes activated,
it functions as an enzyme, cleaving and therefore activating millions of molecules of the next
complement protein in the cascade. In turn, each molecule activates multiple molecules of the next
protein in the cascade, and so on. Generally, activation involves splitting the protein into two parts,
each of which then carries out a specific function. Stringent mechanisms control complement
system activation at various points.
Each of the major complement proteins has been given a number along with the letter C, for
complement. The nine major proteins, C1 through C9, were numbered in the order in which they
were discovered and not the order in which they react. When one of these is split into two
fragments, a lowercase letter is added to the name. For example, the activation of C3 splits it into
C3a and C3b. Note that C3 spontaneously splits into C3a and C3b even when the complement
system has not been activated, but does so at a very low rate; this spontaneous hydrolysis allows
enough C3b to be present to potentially trigger the alternative pathway of complement activation
Activation of the complement system eventually leads to three major protective outcomes:
1. Inflammation: The complement components C3a and C5a induce changes in endothelial
cells that line the blood vessels, and in mast cells. These effects contribute to the vascular
permeability associated with inflammation. C5a is also a potent chemoattractant, drawing
phagocytes into the area where complement was activated.
2. Lysis of foreign cells: Complexes of C5b, C6, C7, C8, and multiple C9 molecules
spontaneously assemble in the membranes of cells, forming doughnut-shaped structures
each called a membrane attack complex (MAC). This creates pores in the membrane,

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disrupting the integrity of the cell. Note that the membrane attack complex has little effect
on Gram-positive bacteria because their peptidoglycan layer prevents the complement
components from reaching their cytoplasmic membrane. The outer membrane of Gram
negative bacteria, however, renders them susceptible.
3. Opsonization: The complement protein C3b binds to foreign material. Phagocytes more
easily “grab” particles coated with C3b because phagocytic cells have receptors for the
molecule on their surface. The material that C3b has coated is said to be opsonized (which
means “prepared for eating”); compounds such as C3b that can opsonize material are
opsonins. Opsonized material may be viewed as carrying a giant “eat me” sign that can be
read by phagocytes. Our own cells are protected from the effects of C3b because our
membranes bind regulatory molecules, leading to the inactivation of C3b when it binds.

Inflammation
When tissues have been damaged, such as when an object penetrates the skin or when microbes
are introduced, a coordinated response called the inflammatory response, or inflammation,
occurs. Everyone has experienced the signs of inflammation; in fact, the Roman physician Celsus
described the four cardinal signs in the first century A.D.—swelling, redness, heat, and pain. A
fifth sign, loss of function, is sometimes present.
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The vital role of inflammation is to contain a site of damage, localize the response, and restore
tissue function. The process recruits neutrophils, followed by monocytes and other cells, to assist
the local macrophages and eosinophils at the site of damage.
The Inflammatory Process
Initiation of the inflammatory process leads to a cascade of events that result in dilation of small
blood vessels, leakage of fluids from those vessels, and the migration of leukocytes out of the
bloodstream and into the tissues.
The diameter of local blood vessels increases during inflammation due to the action of certain pro-
inflammatory chemicals. This results in an increase in blood flow to the area, causing the heat and
redness associated with inflammation, accompanied by a decrease in the velocity of blood flow in
the capillaries. Because of the dilation, normally tight junctions between endothelial cells are
disrupted, allowing fluid to leak from the vessels and into the tissue. This fluid contains various
substances such as transferrin, complement system proteins, and antibodies, and thus helps to
counteract invading microbes. The increase of fluids in the tissues causes the swelling and pain
associated with inflammation. The direct effects of chemicals on sensory nerve endings also cause
pain.

Cell-Mediated Immunity
Cellular immunity is mediated by T lymphocytes, or T cells; their name reflects the fact that they
mature in the thymus. T cells involved in eliminating antigen include two subsets—cytotoxic T
cells and helper T cells. Both of these have multiple copies of a surface molecule called a T-cell
receptor, which is functionally analogous to the B-cell receptor; it enables the cell to recognize a
specific antigen. Unlike the B-cell receptor, however, the T-cell receptor does not recognize free
antigen. Instead, the antigen must be presented by one of the body’s own cells. A third T-cell
subset, regulatory T cells (formerly T suppressor cells), has recently been described and is
currently the focus of a great deal of research. Regulatory T cells are similar to the other T cells in
that they have a T-cell receptor, but their role is entirely different. Instead of fostering a response,
they appear to be critical in preventing the immune system from mounting a response against “self”
molecules, thereby preventing autoimmune diseases.
Like B cells, a T cell must receive confirmation from another cell that the antigen it recognizes
signifies danger before it can be triggered to multiply. The cell type responsible for providing the
“second opinion” to T cells is the dendritic cell, a component of innate immunity. Once activated,
the proliferating T cells differentiate to form effector T cells, which are armed to perform distinct
protective roles. For simplicity and clarity, we will refer to effector helper T cells as TH cells, and
effector cytotoxic cells as TC cells. Like B cells, both types of T cells are able to form memory
cells following activation. These quickly respond if the same antigen is encountered later in life.
In response to intracellular agents such as viruses, TC cells induce the cells harboring the intruder
to undergo apoptosis. While this response obviously harms one’s own cells, the sacrifice of
infected “self” cells ultimately protects the body. For example, destroying virally infected cells

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prevents those cells from being used by the virus to produce and release more viral particles.
Sacrifice of the cells also releases unassembled viral components. This can strengthen the overall
immune response by stimulating production of more antibodies that can then block further cellular
infection
The critical task for the immune system is to distinguish and destroy only those “self” cells that
are infected or otherwise tainted; failure to do this can result in an autoimmune disease. As a means
to facilitate detection of intracellular “corruption,” all nucleated cells of the body regularly display
short fragments of proteins present within their cytoplasm in specialized molecules on their cell
surface. TC cells inspect the peptides being presented. If a “self” cell presents an abnormal protein
that signifies danger, such as a viral protein, a TC cell will induce the presenting cell to sacrifice
itself. TH cells help orchestrate the various responses of humoral and cellular immunity. They
provide direction and support to B cells and T cells, and they direct the activation of macrophages.

T Cell Activation

Adaptive T cell-mediated immunity is driven by activation of T cells: cytotoxic T cells activated

by endogenous antigen to kill infected cells, and helper T cells activated by exogenous antigen to
stimulate macrophage killing of endosomal pathogens. Note that the pathogens targeted by cellular
immunity are protected from antibody and complement binding by their intracellular locations.
Adaptive humoral immunity also usually involves T cell activation to produce cytokines that
stimulate B cell antibody synthesis. Naïve resting T cells are stimulated by antigen peptide
presented on Class I MHC to cytotoxic CD8 T cells or Class II MHC to helper CD4 T cells, along
with co-stimulatory signals from APC, to proliferate and differentiate into clones of fully activated
effector T cells. Only professional APC (dendritic cells, macrophages, and B cells) have both Class
I and Class II MHC and can deliver co-stimulatory signals. Activated T cells perform their effector
functions when they encounter MHC-presented peptide on their target cells.

To activate T cells, APC must deliver two distinct signals, one to TCR via peptide on MHC, and
a second co-stimulatory signal. The professional APC that can provide co-stimulation are
dendritic cells (DC), macrophages, and B cells. Of these cell types, DC deliver the best co-
stimulation and are probably responsible for activating most naïve T cells. APC use the membrane
molecule B7 (B7.1 = CD80 and B7.2= CD86 are slightly different forms of this molecule) to
deliver a co-stimulatory signal through T cell membrane CD28. Signals received through CD28,
when received with antigen signals, activate a T cell. Some antibodies to CD28 can provide co-
stimulatory signals, while antibodies to B7 block the ability of the APC to activate T cells.

Once a T cell becomes activated, it expresses other receptors which enhance co-stimulation. A key
T cell molecule expressed early in activation is CD40 ligand (CD40L). CD40L binds APC CD40
and transmits activation signals to the T cell; T cells in mice that cannot express CD40L cannot go
beyond the early stages of T cell activation. CD40L binding to APC CD40 signals the APC to
express more B7 molecules to provide even more co-stimulation to the T cells; signaling to B cells

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and macrophages through CD40 also promotes their activation. Binding of other inducible
signaling molecules 4-1BB (CD137) and ICOS (Inducible CO-Stimulator) on T cells to 4-1BB
ligand (4-1BBL) and LICOS (Ligand of ICOS) on activated DC, macrophages and B cells also
further activate both the T cell and the APC.

When a T cell becomes activated it expresses CTLA-4 a molecule very similar to CD28 and also
able to bind B7, alongside its CD28 molecules. CTLA-4 binds B7 about 20 times more avidly than
does CD28, and CTLA-4 binding to B7 sends an inactivation signal to the T cell. The immune
response, therefore, depends on the "push" of antigen stimulation to activate T cells into effectors
and the "pull" of negative signals that curtail T cell responses. These combinations of activation
and inactivation signaling mechanisms are common in the immune system and are there to control
a very powerful response that can damage the body if not restricted. Mice born with a defective
CTLA-4 gene suffer from over-proliferation of lymphocytes.

Cytotoxic T Cells
Cytotoxic T cells (CTL) mediate antigen-specific, MHC-restricted cytotoxicity and are important
for killing intra-cytoplasmic parasites that are not accessible to secreted antibody or to phagocytes.
Examples include all viruses, rickettsias (causes of Rocky Mountain spotted fever and typhus),
some obligate intracellular bacteria (Chlamydia), and some protozoan parasites which export their
proteins from macrophage vesicles to the cytoplasm (Toxoplasma gondii). The only way to
eliminate these pathogens is to kill their host cells.

Effector CTL bind their targets first via nonspecific adhesion molecules such as LFA-1 (CD
11a/18), then with specific TCR. TCR-peptide-MHC-CD8 binding reorients the CTL cytoskeleton
to focus release of effector molecules towards the target cell. CTL induce apoptosis in their targets.
Cells undergoing apoptosis undergo chromatin condensation and membrane vesicle shedding.
DNA is cut into pieces in multiples of 200bp, which look like steps on a ladder (and is called a
"DNA ladder") when run on a gel that separates the DNA by size. Fragmented DNA can be
detected in individual cells using the TUNEL assay.

Programming the target cell to die requires only about 5 minutes contact between CTL and target,
although the targets may appear viable for much longer. CTL then dissociate to bind and kill other
target cells presenting the same epitope. During their maturation into effector CTL, CD8 cells
synthesize cytotoxic molecules and store them in cytoplasmic granules for quick release upon
target cell binding. Perforin has sequence homology with complement C9, and polymerizes to
form pores in the target cell membrane through which water and salts can enter. At high perforin
concentrations, this may be enough to destroy the target by osmotic lysis, but physiological levels
of perforin are believed to be too low to induce osmotic lysis. Instead, perforin pores allow
granzymes to enter the target cell. Granzymes are serine proteases which trigger the apoptotic
cascade leading to DNA fragmentation and membrane-bound vesicle shedding. Apoptotic
enzymes activated by granzymes can also destroy viruses or other cytoplasmic pathogens in the
target cells so that the pathogens cannot infect nearby cells. Dead target cells are rapidly ingested
by macrophages without activating macrophage expression of B7, preventing co-stimulation of
any self-specific T cells which bind the self-peptides on macrophage MHC.

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