1) Clonal selection theory states that when a B cell encounters its specific antigen, it is activated to multiply and produce clones that secrete antibodies against that antigen.
2) Effector cells like plasma cells and activated T cells carry out immune responses by secreting antibodies or performing cell-mediated responses.
3) Memory cells are also produced and provide faster secondary immune responses upon reexposure to the same antigen.
2. The theory states that in a pre-
existing group of lymphocytes
(specifically B cells), a
specific antigen only activates
(i.e. selection) its counter-
specific cell so that particular
cell is induced to multiply
(producing its clones) for
antibody production.
This activation occurs in
secondary lymphoid organs
such as the spleen and
the lymph nodes
Clonal selection theory
3. 1) A hematopoietic stem
cell undergoes differentiation and
genetic rearrangement to produce
2) immature lymphocytes with
many different antigen receptors.
Those that bind to
3) antigens from the body's own
tissues are destroyed, while the
rest mature into
4) inactive lymphocytes. Most of
these will never encounter a
matching
5) foreign antigen, but those that
do are activated and produce
6) many clones of themselves.
Clonal selection of lymphocytes
4. Two types of cells are produced by clonal selection
Effector cells and
Memory cells.
Effector cells are the relatively short-
lived activated cells that defend the
body in an immune response.
Effector B cells are called plasma
cells and secrete antibodies, and
Activated T cells include cytotoxic T
cells and helper T cells, which carry
out cell-mediated responses.
The production of effector cells in response to first-time exposure
to an antigen is called the primary immune response.
5. Memory cells also are
produced at this time, but they
do not become active at this
point.
If the organism is reexposed
to the same antigen that
stimulated their formation, the
body mounts a second
immune response that is led
by these long-lasting memory
cells, which then give rise to
another population of identical
effector and memory cells.
. This secondary mechanism is known as immunological memory
6. The effector functions of
the immune system have
both humoral (antibody)
and cellular arms.
Both co-operate to clear
the body of infection and,
in some cases
7.
8. Clonal selection of a B cell
The effector molecules of the humoral branch are antibodies, the
secreted version of the highly specific receptor on the surface of B
cells.
9. The humoral arm of the immune system refers to the
activities of antibodies secreted by B lymphocytes.
The antigen specificity,
isotype, and
interactions with FcRs
are all important features of antibody effector function.
Antibody-binding receptors,
which bind to the constant
regions of antibodies and are
therefore called Fc receptors
or FcRs, determine which cells
an antibody can recruit to aid in
its destructive mission
10. Antibodies Mediate Effector response
Antibodies inhibit and clear infection
By blocking the ability of pathogens to infect
(neutralization),
11. By coating pathogens so that they are recognized and
phagocytosed by innate immune cells (opsonization),
By recruiting complement to the pathogen (complement
fixation), and
12. By directing other cells of the innate immune system to kill
infected cells (antibody-dependent cell cytotoxicity).
Antibody-dependent Cell Cytotoxicity
14. Each antibody isotype has different effector functions:
IgM and some IgG antibodies fix complement
IgG antibodies mediate ADCC
IgE antibodies induce release of inflammatory
molecules from granulocytes to kill parasites
IgA antibodies are a major isotype in bodily secretions
and block entry of bacteria and toxins to the bloodstream.
Antibody isotype
15. Phagocytosis of antibody antigen complexes by
macrophages
Fc receptors are responsible
for many of the effector
functions of antibodies.
16. Transcytosis of antibodies through epithelial cell layers
PolyIg receptors (PolyIgR)
expressed by the inner
surface of epithelial cells
will bind dimers and
multimers of IgA and IgM
antibodies and transfer
them through the cell to
their apical (outer) surface
and into the lumen of an
organ (e.g., the GI tract).
This is a process referred to as transcytosis and is responsible
for the accumulation of antibodies in bodily secretions.
17. Lysis of antibody bound infected cells by NK cells (ADCC);
protecting serum antibodies from degradation.
regulating the activities of innate immune cells.
18. FcRs are expressed by many cell types in the body and
generate signals when bound to antibody-antigen
complexes.
FcR generated signals can either activate or inhibit the activity
of cells.
Whether an FcR is activating or inhibiting depends on whether it
includes or associates with an ITAM (activating) or an ITIM
(inhibiting) protein motif
Immunoreceptor tyrosine-based inhibition motif (ITIM)
immuno-receptortyrosine activation motif (ITAM).
Conserved sequence of amino acids that is found in
the cytoplasmic tails of many receptors of the immune
system
19.
20. Most FcRs are activating receptors and are associated with signaling
proteins that contain the Immuno-receptorTyrosine Activation Motif
(ITAM).
FcγRIIB is an inhibiting FcR and includes an Immunoreceptor
Tyrosine Inhibition Motif (ITIM) in its intracellular region
Antibody-binding polypeptides – blue
Accessory signal-transducing polypeptides- green.
21. The effector cells of the cell-mediated immune system include
cells of the innate immune system
(natural killer [NK] cells)
cells of the adaptive immune system
Helper CD4T cells (TH cells) and
CD8 cytotoxic T lymphocytes (CTLs or TC cells).
.
Cell mediated effector response
NKT cells are also participants and have features of both the
innate and adaptive immune systems
22. Cellmediated immunity consists of both helper T cells (CD4
TH) and several types of cytotoxic cells.
Stimulation of immune response by activated helper T cells
23. Effector cytotoxic cells arise from both the adaptive and innate
immune systems and, therefore, include both antigen-specific
and -nonspecific cells
Antigen non-specifi c
(innate immune) cells
that contribute to the
clearance of infected
cells include NK cells
and non lymphoid cell
types such as
macrophages,
neutrophils, and
eosinophils
Antigen-specific cytotoxic
cells include CD8 T
lymphocytes (CTLs or TC
cells), as well as the CD4
NKT cell subpopulation
Populations of cytotoxic
CD4 TH cells may
contribute to delayed-type
hypersensitivity.
24. Naïve TC cells are incapable of killing target cells
(also referred to as CTL precursors (CTL-Ps) to denote their
functionally immature state.
Only after a CTL-P has been activated does the cell
differentiate into a functional CTL with cytotoxic activity.
Cells of the adaptive immune system
25.
26. In order to become functional CTLs, naïve TC precursors
(CTL-Ps) must engage with APCs that have been previously
activated (licensed).
CD4 T-cell help is not necessary for this first activation
step, but is required for optimal generation of memory and
proliferation of CTLs.
This involves 3 signalling steps.
27. An antigen-specific signal transmitted by the TCR complex
upon recognition of a class I MHC-peptide complex on a
“licensed” APC.
28. A costimulatory signal
transmitted by the CD28-
CD80/86 (B7) interaction of
the CTL-P and the licensed
APC
A signal induced by the
interaction of IL-2 with the
high-affinity IL-2 receptor,
resulting in proliferation and
differentiation of the antigen-
activated CTL-P into effector
CTLs
IL-2 can be generated by helper T cells as well as by the CD8 T
cell itself.
29. Antigen-specific effector T cell populations can be identified
and tracked by labeling with MHC tetramers
MHC tetramers
A homogeneous population of peptide-bound class I MHC molecules is
conjugated to biotin and mixed with fluorescently labeled streptavidin
In the ideal situation,
four biotinylated
MHC-peptide
complexes bind to the
high-affinity binding
sites of fluorescent
streptavidin to form a
tetramer.
.
30. Addition of the now fluorescent tetramer to a population of T cells
results in binding of the fluorescent tetramer only to those
CD8 T cells with TCRs that are specific for the peptide-MHC
complexes of the tetramer
31. CTLs induce cell death via the following mechanisms:
Directional release of granule contents
Granzyme and perforin mediated cytolysis
The fas-fasl pathway.
Both trigger apoptosis in the target cells
33. The perforin-mediated cytotoxic response of CTLs involves
several steps:
TCR-MHC mediated recognition of target cells
Formation of CTL/target-cell conjugates and immune
synapse formation
Repositioning of CTL cytoplasmic granules toward the
target cell
Granule release
Formation of pores in the target-cell membrane
Dissociation of the CTL from the target
Death of the target cell
Granzyme and perforin mediated
cytolysis
Fas-mediated killing also involves conjugate and immune synapse
formation where Fas-FasL interactions occur.
37. Other non antigen-specific cells of the innate immune
system (NK cells and granulocytes) can also kill target
cells via antibody-dependent cell-mediated cytotoxicity
(ADCC), resulting in the release of lytic enzymes, perforin,
or TNF that damage the target-cell membrane.
NK cells induce apoptosis of tumor cells and virus infected
cells by mechanisms similar to CTLs (perforin induced pore
formation, as well as Fas-FasL interactions), but are
regulated by distinct receptors.
cells of the innate immune system
38. How NK cells distinguish self from non (or altered) self.
It was proposed that NK cells kill when they do not
perceive the presence of normal self-proteins on a cell, the
missing self model
Missing self model.
NK cells kill those cells that
have lost or reduced their levels
of MHC class I, a ubiquitously
expressed self protein— a
phenomenon described by the
missing self model.
39. Model of how cytotoxic activity of NK cells is
restricted to altered self cells
An activating receptor on NK cells interacts with its ligand
on normal and altered self cells, inducing an activation
signal that results in killing.
40. Engagement of inhibitory nk-cell receptors such as
inhibitory kirs and CD94-NKG2 by class I MHC molecules
delivers an inhibition signal that counteracts the activation
signal.
NK cell killing is regulated by a balance between positive
signals generated by the engagement of activating NK receptors
and negative signals from inhibitory NK receptors
41. NK-cell receptors fall into two major structural groups based on
their extracellular regions:
the lectin-like receptors and
the Ig-like receptors.
Whether receptors are activating or inhibiting depends on
their intracellular regions:
•ITAM expressing receptors are activating,
•ITIM expressing receptors are inhibiting.
42.
43.
44. NKT cells have characteristics common to both T
lymphocytes and NK cells
NKT cells do not form memory cells.
most express an invariant TCR and markers common to NK
cells.
They exhibit both helper and cytotoxic activity and kill cells
predominantly via FasL-Fas interactions.
NKT cells
45.
46. Immune cell cytotoxicity can be measured in vitro by
Mixed lymphocyte reaction (MLR), or
Cell-mediated lympholysis (CML) via
radioactivity or fluorescence.
They can be assessed in vivo by
Graft versus host (GVH) responses
Increases in spleen size (splenomegaly).
Editor's Notes
Clonal selection theory is a scientific theory in immunology that explains the functions of cells (lymphocytes) of the immune system in response to specific antigens invading the body.
Each member of the clone carries the same antigen receptor and hence has the same antigen specificity as the original lymphocyte.
However,
and it is responsible for the lifetime immunities to diseases such as measles that arise from childhood exposure to the causative pathogen
How an antibody contributes to clearing infection depends on its isotype, which determines whether it can recruit complement
Receptors that bind to the Fc portion of antibodies are called“Fc receptors”.
Antibody-antigen complexes are bound by Fc receptors on NK cells and granulocytes, thus directing the cytotoxicity of these cells toward the antigen targeted by the antibody (e.g., viral proteins on the surface of an infected cell), and inducing apoptosis of the target cell
Four broad categories of antibody eff ector functions
Antibodies can come in different varieties known as isotypes or classes. In placentalmammals there are five antibody isotypes known as IgA, IgD, IgE, IgGand IgM.
Antibodies protect by recruiting other effector functions through the interaction of CH domains with other cells and proteins of the immune system.Different antibody isotypes recruit different effector functions.
ncluding
An immunoreceptor tyrosine-based inhibition motif (ITIM), is a conserved sequence of amino acids (S/I/V/LxYxxI/V/L) that is found in the cytoplasmic tails of many inhibitory receptors of the immune system
The antibody-binding polypeptides are shown in blue and, where present, accessory signal-transducing polypeptides are shown in green.
If antibodies were the only agents of immunity, intracellular pathogens, which occupy spaces that antibody cannot access, would likely escape the immune system. Fortunately there is another eff ector branch of our immune system, cell-mediated immunity, which detects and kills cells that harbor intracellular pathogens.
TH cells exert their eff ector functions indirectly, by contributing to the activation of antigen-presenting cells, B cells, and cytotoxic T cells via receptor-ligand interactions and soluble cytokines and chemokines. On the other hand, cytotoxic cells exert their eff ector functions directly, by attacking infected cells and, in some cases, the pathogens themselves.
displays some useful features of innate immune cell types, too.
Compared with naïve TH and TC (CTL) cells, effector cells are more easily activated, express higher levels of cell-adhesion molecules, exhibit diff erent traffi cking patterns, and produce both soluble and membrane effector molecules
is conjugated to biotin and mixed with fluorescently labeled streptavidin
T-cell receptors on a CTL interact with processed antigen-class I MHC complexes on an appropriate target cell, leading to formation of a CTL-target cell conjugate. The microtubule organizing center (MTOC) polarizes to the site of interaction, repositioning the Golgi
stacks and granules toward the point of contact with the target cell, where the granules’ contents are released by exocytosis. After dissociation of the conjugate, the CTL is recycled and the target cell dies by apoptosis.
Expression of class I molecules on normal cells (a) thus prevents their destruction by NK cells. Because class I expression is often decreased on altered self cells (b), the killing signal predominates, leading to their destruction.
However,
Th e exact role of NKT cells in immunity remains to be defi ned