Effector functions of immune system

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

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

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.

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

 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

Effector functions of immune system

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.

 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

Antibodies Mediate Effector response
Antibodies inhibit and clear infection
 By blocking the ability of pathogens to infect
(neutralization),

By coating pathogens so that they are recognized and
phagocytosed by innate immune cells (opsonization),
By recruiting complement to the pathogen (complement
fixation), and

By directing other cells of the innate immune system to kill
infected cells (antibody-dependent cell cytotoxicity).
Antibody-dependent Cell Cytotoxicity

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

Phagocytosis of antibody antigen complexes by
macrophages
Fc receptors are responsible
for many of the effector
functions of antibodies.

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.

Lysis of antibody bound infected cells by NK cells (ADCC);
protecting serum antibodies from degradation.
 regulating the activities of innate immune cells.

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

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.

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

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

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.

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

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.

An antigen-specific signal transmitted by the TCR complex
upon recognition of a class I MHC-peptide complex on a
“licensed” APC.

 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.

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.
.

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

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

Directional release of
granule contents

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.

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

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.

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.

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

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.

 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

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).

Effector functions of immune system

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