CELLULAR RESPONSES OF ADAPTIVE IMMUNITY

( IMMUNOLOGY COURSE)

By

Dr. ADEBAYO ISMAIL ABIOLA

(PhD USM Penang)
 B lymphocytes and the antibody response
• When antigen binds to a B cell receptor, the B cell will be triggered to
respond.
• However, in some cases, the B cell requires confirmation by effector T
helper cells whether the antigen truly deserves a response before it
responds.
• Compounds or antigens that elicit a response by B cells only with the help
of the effector T helper cells are called T-dependent antigens.
• The T-dependent antigens are usually proteins.
• Compounds or antigens that elicit or stimulate response by B cells without
the assistance of effector T-helper cells are called T-independent antigens.
• T-independent antigens are generally lipids and carbohydrates.
 The Response to T-Dependent Antigens
• When a T-dependent antigen binds to a B-cell receptor, the B-cell encloses the antigen and
internalizes it.
• The B cell encloses it in a membrane-bound vacuole inside the cell.
• Within the vacuole, the antigen is degraded into peptide fragments, and the peptide fragments a
loaded into the groove of MHC class II molecules to be presented at the cell surface.
• Once the peptides are presented on the B cell, the effector T-cell examines them if they are from
antigen or from self cell.
• T cell receptor binds to the peptides generated from antigen and thereby stimulates the B cell.
• Effector T-helper cell stimulates the B cell by delivering cytokines to the B cell.
• The activated or stimulated B cell will begin to proliferate.
• Some of the progeny resulting from the proliferation will differentiate into plasma cells.
• The plasma cells can be regarded as effector B cells.
• The effector B cells are highly specialized in antibody production.
• The effector B cells produce thousands of antibody molecules per second.
• After the cells produce the antibodies, they die.
Properties of the primary response
• Before a significant amount of antibody can be detected in the blood, a lag
period of 10 days to 2 weeks occurs following the primary (first) exposure
to an antigen.
• During this period of delay, the affected individual could experience some
symptoms of an infection.
• Some of these symptoms could be life threatening.
• However, the immune system is actively responding during this time.
• The plasma cells from the B cells are actively producing antibodies.
• And some of the proliferating B cells undergo changes that enhance the
immune response over time.
• The changes the B cells undergo are affinity maturation, class switching,
and memory cell formation.
Affinity maturation
• This is a form of natural selection that occurs among proliferating B cells
based on the accuracy of their response with respect to antibody
specificity.
• During proliferation of the B cells, certain mutations occur in the region of
the genes of the antibody as activated B cells replicate their DNA just
before they divide.
• This mutation causes some changes in the antigen binding site of the
antibody (and of course the B cell receptor)
• B cells that bind antigens more tightly, for the longest period will continue
to proliferate, while others will undergo apoptosis.
Class switching
• With the directions of the cytokines produced by effector T-helper
cells, some differentiated B cells (plasma cells) could be programmed
to produce antibodies other than IgM.
• This changes alter the class of antibody produced by plasma cells that
descend from these B cells.
• It is very common that circulating B cells can switch to IgG production.
• B cells that are found in the mucosal-associated lymphoid tissues
(MALT) usually switch to IgA production.
Memory cell formation
• Some of the B cells that have undergone class switching will develop
to form memory cells.
• Memory B cells persist in the body for years.
• The memory cells are present in the body in abundant quantity that is
sufficient to provide effective and prompt secondary response when
the same antigen is encountered again in future.
 Properties of the secondary response
• The secondary response is more effective and significantly faster than the primary
response.
• Usually, the repeat invading microbes are eliminated before they cause any obvious harm.
• This explains why an individual who has recovered from a particular disease usually
possesses a long-lasting immunity to that disease.
• Memory B cells are responsible for the effectiveness and potency of the secondary
response.
• There are more memory cells (memory B cells and memory helper T cells) that can
respond to a particular antigen.
• The memory B cells can even scavenge low concentrations of antigens because the
receptors have been refined via affinity maturation.
• The antibodies coded for by these memory cells bind antigen more effectively.
• When memory cells are activated, some of them will differentiate to form plasma cells.
• The plasma cells will rapidly produce antibodies.
• The antibodies produced can be IgG or IgA.
The response of T-Independent antigens
• T-independent antigens stimulate the antibody response by activating B
cells without the assistance of effector T-helper cells.
• The T-independent antigens are fewer than T-dependent antigens but they
are medically relevant.
• The arrangement of the evenly-spaced epitomes of polysaccharides makes
it an antigen that can elicit antibody response without the aid of effector T-
helper cells.
• The arrangement of the epitomes enables clusters of B cell receptors to
bind the antigens through the epitomes simultaneously, which results to B
cell activation without the involvement of effector T helper cells.
• Another example of T-independent antigen is the lipopolysaccharide (LPS)
of Gram-negative bacteria.
T lymphocytes: Antigen Recognition and
Responses
General characteristics of T cells
• T cell have multiple copies of a receptor called T cell receptor (TCR).
• The TCR has two polypeptide chains, which can either be a set of alpha and beta
or gamma and delta.
• Each of the chains has two regions – a variable region and a constant region.
• Unlike the B-cell receptor, the T-cell receptor does not interact directly with free
antigen.
• Rather, the antigen must be presented by another host cell.
• The host cells first process the antigen by degrading its proteins to peptides.
• The peptides are then loaded to the groove of certain proteins called major
histocompatibility complex (MHC) molecules on the surface of the presenting
cell.
• The two types of MHC molecules are MHC class I and MHC class II
molecules.
• MHC class I molecules present endogenous antigens and MHC class II
molecules present exogenous antigens.
• All nucleated cells produce MHC class I molecules except some
specialized cells.
• These specialized cells are dendritic cells, macrophages and B cell.
These specialized cells produce MHC class II molecules.
• These specialized cells are called antigen-presenting cells (APCs).
• There are two functional types of T cells – T cytotoxic cells and T helper
cells.
 Activation of T cells for immune responses
• The activation of T-cell is largely mediated and influenced by the dendritic cell.
• The skin, mucosa and other peripheral tissues are the primary locations or sites
of immature dendritic cells.
• The dendritic cells use pinocytosis and phagocytosis to engulf foreign solid
particulate and soluble materials that could restrict and contain foreign
proteins.
• The dendritic cells that reside just below the mucosal barriers to collect
materials from the digestive and respiratory tracts by protruding and projecting
their tentacle-like extensions between the epithelial cells of the barriers of
mucosa.
• Dendritic cells do have specific receptors such as toll like receptors (TLRs) and
others that enable them to sense and recognize pathogens,
• Once the cells recognize pathogens and foreign materials, they take them up
and moves to the secondary lymphoid organs where they will encounter naive T
cells.
• The dendritic cells becomes mature to antigen presenting form, able to
present antigen to naïve T cells as during their movement to the
secondary lymphoid organs.
• The mature antigen presenting dendritic cells synthesize co-stimulatory
molecules that are surface proteins.
• The co-stimulatory molecules acts a s ‘emergency lights’ that interact with
the T cell. The interaction is a form of communication by the molecules to
T cells that the antigen (or foreign material) being presented indicates
danger. Then, the naive T cell become activated.
• On the contrary, naive T cells that recognize antigen presented by a
dendritic cell that do not display co-stimulatory molecules become
anergic and consequently undergo apoptosis.
• Dendritic cells can present peptides on both MHC class I and class II
molecules regardless of the origin of the peptides, hence they are called
cross presenters.
• This cross-presenting ability of dendritic cells allows them present antigen
to cytotoxic T cells and helper T cells to activate both cells.
• Activated T cells will undergo clonal selection and expansion,
subsequently forming effector cells and memory cells.
• The effector and memory T cells can exit the secondary lymphoid organs
and circulate in the bloodstream, through which they can enter tissues,
especially at the sites of infection.
• It is suggested or proposed that B cells and macrophages should be able
to activate naive T cells because they can present antigens on MHC class II
molecules, and they can produce co-stimulatory molecules.
• However, in vivo studies proved that macrophages and B cells do not have
interactions with naive T cells, but they interact with memory T cells,
hence they probably activate memory T cells during secondary response.
 Functions of Effector T-cytotoxic (CD8) cells
• Effector T-cytotoxic cells induce apoptosis or programmed cell death in
‘self’ cells that are infected with virus or other intracellular
microorganisms.
• They also destroy host cells that have become cancerous.
• Furthermore, effector T-cytotoxic cells produce some cytokines that
sensitizes neighboring cells to become more alert and sensitive against
intracellular invading microbes or pathogens.
a. For instance, one of the cytokines produce by effector T-cytotoxic cells
stimulate processing and presentation of antigen in nearby cells, which
enables the effector T-cytotoxic cells to detect the infected cells.
b. Another example is the effector T-cytotoxic cell produced cytokine that
can selectively activate local macrophages whose toll-like receptors
have been stimulated.
• All nucleated cells regularly degrade various proteins in their cytoplasm.
• The peptides of the degraded proteins are loaded into the groove of newly
synthesized MHC class I molecules to be delivered to the cell surface.
• The proteins are called endogenous proteins because they originated from the
cytoplasm of the host (intracellular).
• If a host cell is not infected or cancerous, all the proteins that will be presented
by MHC class I molecules will be that of the normal proteins of the host cells,
which the immune system will recognize as ‘self’.
• Normally, effector T-cytotoxic cells do not recognize the peptides of the normal
proteins of the cells presented by the MHC class I molecules.
• However, if the cell is infected by virus or an intracellular microbe, some of the
proteins of the invaders will be degraded and presented by MHC class I
molecules on the cell surface, the effector T cytotoxic cells will recognize the
proteins.
• Also, if the cell becomes cancerous, certain abnormal proteins will be presented
by the MHC class I molecules and they will be recognized by the effector T-
cytotoxic cells.
• Once the effector T-cytotoxic cells recognized the presented peptides, the T-
cytotoxic cells will establish intimate contact with the infected or cancerous
cell and released pre-formed cytotoxins directly to the cells.
• The cytotoxins contain molecules and substances that are lethal to the cells.
• The cytotoxins have perforin and proteases.
• Perforin is a molecules that create pores in cell membranes and make the
membranes highly permeable.
• Proteases are a group of various proteins that enhance or enable apoptosis
to occur in cells.
• So, the perforin creates pores in the membrane to allow proteases enter the
inner part or cytoplasm of the cells and facilitate apoptosis of the cell.
• The remains of the apoptotic cell are then quickly phagocytosed by the
macrophages .
• The effector T-cytotoxic cell can then proceed to attack other infected or
cancerous cells.
 Functions of effector T-helper (CD4) cells
• Effector T-helper cell are responsible for determining the significance of
antigen presented by a specialized group of cells commonly referred to as
antigen presenting cells (APCs) or professional antigen presenting cells.
• The APCs have a type of MHC molecule called MHC class II molecules.
• The MHC class II molecules of APCs present antigens to T-helper cells for
evaluation and recognition.
• The peptides presented by MHC class II are exogenous antigens or peptides
because they originated outside of the cell.
• B cells and macrophages are examples of APCs and both of them can process
extracellular antigens for presentation.
• There are two subsets of T-helper cells, which are Th1 and Th2.
• The Th1 and Th2 interact with different antigen-presenting cells.
• Th1 judge and recognizes the antigen presented by macrophages.
• If Th1 recognizes the antigen or peptide presented by macrophages, it activates that
macrophage.
• Th1 are key in stimulating or triggering other parts of adaptive immune responses.
• Th1 release various cytokines that trigger proliferation of effector T cells, activate
natural killer cells, increase production of monocytes in the bone marrow, recruit
macrophages to the site, and influence changes in endothelial cells that allow
diapedesis of the phagocytes from the blood vessels to the site.
• Some microbes and invaders avoid destruction by phagocytosis even after they have
been engulfed by phagocytes.
• These allow the microbes to survive and even multiply in the phagocytes.
• Th1 recognizes the macrophages that have such microbes which have evaded the
destruction process by the phagocytes.
• Th1 activates such macrophages by delivering cytokines that stimulate more potent
destructive mechanisms.
• If the response is not enough, group of macrophages can fuse together to form giant cells
and exert more lethal mechanisms to get rid of the invader.
• If additional lethal activity is needed, the giant cells together with T cells can unite to
form granulomas.
• The granulomas will contain the invader and prevents it from infecting other host cells.
• When macrophages engulf microbes, it forms phagosome within it.
• In the phagosome, some of the proteins of the engulfed microbe will be degrades and
presented by MHC class II to the T-helper cells at the cell surface.
• Once the T helper cell recognizes the displayed peptides, the T helper cell establishes
close contact with the cells.
• Then, the T helper cell begins to synthesize cytokines and it delivers the cytokines to the
macrophage to stimulate the macrophage.
• Once the macrophage is stimulated or activated, there will be changes in the physiology
and morphology of the macrophage.
• The macrophage enlarges, its plasma membrane becomes irregular and ruffled, and it
increases the rate of its metabolisms so that the number of lysosomes it generates
increases.
• Eventually, the toxic chemicals in the lysosomes destroy or kill the invading microbes.
• Th2 cells judge and recognize antigen presented by B cells.
• If Th2 recognizes the antigen presented by B cells, it activates the B cell.
• Th2 supports proliferation and class switching by activated B cells.
• When a naive B cell binds antigen through its B cell receptor, the cell internalize
the antigen.
• It encloses the antigen in a membrane-bound vesicle called endosome.
• The proteins of the antigen in the endosome are degraded to peptides.
• The peptides are loaded to the groove of MHC class II molecules and are
presented for recognition.
• Th2 cell recognizes the presented peptides and maintain an intimate contact
with the B cell that presented the peptides.
• The, the Th2 synthesizes cytokines and delivers them to the B cell.
• The B cell is activated by the cytokines and makes it proliferate.
• The proliferated B cells will undergo affinity maturation and class switching.
• The cytokines also stimulate the formation of memory cells.
 Natural killer (NK) Cells
• The activities of natural killer cells augment the adaptive immune response.
• NK cells are important in the process of antibody-dependent cellular cytotoxicity (ADCC).
• ADCC is a means of killing cells that binds to antibody.
• The activity of NK cells provides mechanisms to destroy large parasitic organisms which can
not be ingested by phagocytes due to their large sizes.
• Also, NK cells’ activity can kill host cells which have foreign protein materials embedded into
their membranes such as the cells that are infected by some specific viruses.
• NK cells recognizes and binds to their target by means of Fc receptors that are abundant on
their surfaces.
• The Fc receptors bind the Fc portion (red flag portion) of the antibodies that are attached to
the target cells.
• When multiple Fc receptors binds the Fc regions, the NK cells delivers certain granules (which
contain proteases and perforin) directly to the target cells.
• The perforin and proteases can kill foreign cells and induce apoptosis of ‘self’ cells.
• NK cells can also recognize and kill host cells that do not possess MHC class
I molecules on their surfaces.
• Some viruses have mechanisms to circumvent the activity of T cytotoxic
cells by disrupting the process of antigen presentation. When these kind of
viruses infect host cells, the infected host cells barely have MHC class I
molecules.
• Therefore, they can not be targets of T-cytotoxic cells.
• The NK cells can correctly recognize the absence of MHC class I molecules
and induce or trigger apoptosis in those cells.
• The main reason for this activity of NK cells is that NK cells are
programmed to destroy ‘self’ cells.
THANK YOU FOR
LISTENING