Chapter 6

Effector cells of the immune system

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 Effector Cells of the Immune
System

• Objectives of the lesson

• Up on successful completion of this lesson
students will be able to:-
 List down the effector cells of the immune system
 Differentiate the specific function of effector cells
of the immune system
 Differentiate the different type of cytokines
 Locate the activity of cytokines in the immune
response

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Blood Cells

T
Lymphoid Lymph
progenitor cell ocytes
B
Lymphoc
ytes

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 Effector Cells of the Immune
System
• Monocytes and Macrophages
 Monocytes circulate in the blood after leaving the bone
marrow.

 Monocytes usually circulate in the blood for only a day or so

before they enter the tissue to mature into macrophages.

 Monocyte production and release from the bone

 marrow is increased during an immune response.

 Under normal conditions, monocytes enter the tissues as

resident macrophages in various locations (such as the skin,
lung, liver, spleen, bone marrow and peritoneal cavity)

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 Effector cells…

 The cells enlarge, allowing greater phagocytosis

and they increase the amount of digestive
enzymes (lysosyme) in their intracellular vesicles
(lysosomes) thus facilitating microbe degradation.

 In the tissues, macrophages live for months and

are motile (using pseudopods to move like
amoebae).

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 Effector cells…

 These fixed, resident macrophages play an

important role in keeping the tissues clear of
antigen and debris.

 More monocytes are rapidly recruited as needed

to these and other sites.

 When monocytes enter the tissues and become

macrophages they undergo several changes.

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 Effector cells…

 Macrophages are usually in the resting state

unless activated during an immune response.

 Activation of these cells may happen in response

to Th-derived cytokines (especially IFN-γ) or from
contact with bacteria or bacterial products.

 Phagocytosis of pathogens also stimulates

activation.
 The activated state is characterized by more
efficient phagocytosis and killing of microbes.

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 Effector cells…

 There are three major roles that macrophages play in

the immune response to pathogens.

 The first is their very important role in phagocytosis. In

this role they recognize and remove unwanted
particulate matter including products of inflammation
and invading organisms, immune complexes, toxins
and dying cells.

 The large number of macrophages in the spleen and

liver (where they are called Kupffer cells) are
particularly important for removal of bacteria from the
bloodstream.
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 Effector cells…

 The second important role macrophages play is as antigen

presenting cells (APC) during secondary immune responses.

 Although they are very poor at activating naive T cells they

are very good at activating memory T cells.

 The great advantage of this is that circulating memory T

cells which are rapidly drawn to the site of infection can be
immediately activated by macrophages without antigen
being transported to the local draining node for presentation
to T cells.

 Their third role is cytokine secretion

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 Effector cells…

 After activation, these cells secrete important

inflammatory cytokines such as IL-1, IL-6 and
TNF-α. IL-1 and TNF act to recruit neutrophils and
more monocytes from the circulation as well as
having systemic effects (such as fever).

 In chronic inflammation, macrophages act as

scavengers and can become giant cells (via cell
fusion) which help form granulomas.

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Natural Killer Cells

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 Effector cells…
• Natural Killer Cells
 These cells are sometimes called large granular
lymphocytes (LGL's) because they are large,
granular and lymphocytes

 NK cells have some surface markers in common

with T cells, and they are also functionally similar
to cytotoxic T lymphocytes (CTL). Like CTL, NK
cells are particularly important in the killing of
cellular targets (such as tumor cells or virus-
infected cells).

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 Effector cells…
• Natural Killer Cells
 Unlike CTL, however, the killing by NK cells is not
antigen specific, they do not need to recognize
specific antigen presented by MHC on the target
cell.

 In fact, it is the very presence or absence of Class

I MHC that appears to be involved in NK cell
activation.

 It is thought that many tumor cells are too busy

proliferating to bother about expressing the
normal surface molecules at normal levels.
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 Effector cells…

 The lack of normal levels of Class I MHC on the surface of

tumor cells is sufficient to activate NK cells to kill them.

 NK cells do not have a T cell receptor and are not T cells

but they kill target cells in the same manner as CTL kill
targets.

 However, they also produce large amounts of tumor

necrosis factor alpha (TNF-α).

 This factor has many functions but one important one in

this context is that it binds to the TNF
receptor on target cells and induces apoptosis.

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 Effector cells…

 Recent data have shown that NK cells also

produce a lot of IFN-γ, which is very interesting
since this cytokine activates macrophages and
stimulates them to produce large amounts of
TNF-α.

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 Neutrophils

• Neutrophils are produced in the bone marrow

from the granulocyte-monocyte stem cell.
• These cells are often called polymorphonuclear
cells (PMN's).
• This is because of the polymorphic shape of the
nucleus.
• Sometimes the terms neutrophil and PMN are
used interchangeably.

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 Nuetrophils…..

 Neutrophils are the most common white blood cells

in the circulation, making up about 60-70% of the
total WBC count.

 They are very short-lived cells, circulating in the

blood for about 8 hours after their release from the
bone marrow

 If induced to migrate out of the blood into the

tissues, they will engage in a variety of effector
functions before dying by apoptosis within 1-2
days
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 Nuetrophils…..
 Neutrophils are attracted into the tissue by
chemotactic factors that include Complement
proteins, clotting proteins, cytokines and
chemokines.

 They are the first cells to arrive at the site of

inflammation by leaving the blood, through the
endothelium into the tissue (called “transmigration”
or “emigration”).

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 Nuetrophils…..

• The appearance of neutrophils in the tissue is

associated with bacterial infection, acute tissue
injury, immune complex-Complement activation,
necrosis and tissue remodeling.
• In the tissues, neutrophils are very active phagocytic
cells.

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 Nuetrophils…..
 They are the most effective at killing ingested
microorganisms and can do this by oxygen
dependent pathways (such as superoxide anion (O2)
and hydrogen peroxide (H2O2), nitrogen dependent
pathways (nitric oxide (NO) or independent
pathways (such as defensins and digestive
enzymes).

 Neutrophils, however, do not normally act as antigen

presenting cells.

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 Eosinophils

 Eosinophils are named because of their intense

staining with 'eosin'.

 Under the microscope, eosinophils typically have

a bi-lobed nucleus and contain many basic crystal
granules in their cytoplasm.

 The granules are eosinophil mediators that are

toxic to many organisms and also to tissues.

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 Eosinophils

 Eosinophils circulate in the blood and emigrate into

tissues, are phagocytic, and have been linked with
anti-parasite immunity.

 Recently, eosinophils have been suggested to play a

major role in the lung pathology associated with the
late phase of asthma.

 There is also some evidence that they may be

involved in immune responses against breast and
colon tumors.

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 Mast Cells
 Mast cells are formed in the tissue from undifferentiated
precursor cells released into the blood from the bone
marrow.

 They are not the tissue counterparts of basophils but

they are similar in many respects.

 Mast cells contain numerous granules with preformed

mediators which can be released from mast cells after
stimulation.

 The preformed mediators include histamine and other

active substances, including some cytokines (such TNF-
α).

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 Mast cells…

 Stimulation of mast cells also results in the production of

newly formed mediators such as prostaglandins and
leukotrienes.

 Stimulation of mast cells occurs in several ways such as

by the anaphylatoxins (C3a and C5a) of the Complement
system or by the cross-linking of surface IgE.

 Mast cells have high affinity Fc receptors for the IgE that
is produced against an allergen.

 As a result, mast cell release is most significant in either

acute inflammation or in allergic responses.

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 Basophils

 Basophils are found in low numbers in the blood.

Their functions are not well understood but they
are known to be involved in Type I
hypersensitivity
(allergic) responses.

 These cells have high affinity Fc receptors for IgE

on their surface.

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 Basophils

 Cross-linking of the IgE causes the basophils to

release pharmacologically active mediators such as
heparin and histamine.

 Basophils, therefore, act very much like mast cells

except that they are in the blood instead of the
tissues.

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Advanced immunology 27
 Cytokines

 Cytokines are proteins that function as chemical

messengers in the immune system.
 The immune system is a network with several parts that
work together to protect your body from threats, like
germs that can make you sick.
 It contains immune cells that fight invading pathogens
(like viruses and bacteria), allergens and other harmful
substances that enter your body.
 Cytokines signal those immune cells to fight the
invaders.
 Generally Cytokines are the protein messenger
molecules produced by these cells in order to
communicate and orchestrate the attack.
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 Cytokines
 Cytokines are small, secreted, non-antibody proteins
 produced by cells involved in both innate & adaptive
 immunity
 mediate and regulate immunity, inflammation, and
hematopoiesis
 Chemokines, interleukins and growth factors are
subfamilies of the cytokine family.

 Just as hormones in the endocrine system can

produce an effect on other cells, so cytokines can act
on other immune cells, especially cells that are close
by.

 Cytokines also act on non-immune cells, such as the

blood vessel endothelium.
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 Cytokines …

o Cytokines have several important characteristics:

1. the same cytokine may be made by a number of
different cells.

2. the same cytokine may have different effects in

different circumstances (this is called 'pleotropy')

3. different cytokines may have the same activity

depending on the situation ('redundancy').

4. cytokines often act together and increase the

effects of one another ('synergy').

5. They may also act as antagonists.

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 Cytokines….

 most cytokines have either paracrine or autocrine

effects.

 Paracrine means they act on cells near to them or that

they are actually touching.

 The autocrine function of IL-2 is well known because,

when a T cell is stimulated to make IL-2, it stimulates
itself via the IL-2 receptor to proliferate.

 An example of an uncommon endocrine function for

cytokines is IL-1 which can cause fever by stimulating
the hypothalamus
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 Cytokines….

 Originally, the cytokines were named according to their

function (like T cell growth factor, now called IL-2) but
then the pleotropy of cytokines was
observed, making function-specific names
confusing.

 After more and more cytokines were identified, and in

order to avoid confusion, immunologists started
naming some of the cytokines 'interleukins' (or IL for
short) and numbering them as they were found.

 The first interleukin identified therefore

was IL-1 and the most recent one is IL-25.
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 Cytokines….

Interleukin 1 (IL-1)
 Interleukin 1 has many functions on many
different cells and is secreted by a number of
cells including macrophages, monocytes and
dendritic cells.
 An important stimulus for IL-1 production by the
macrophage is the presence of microbial
products.
 IL-1 (originally described as T cell activation
factor) helps to activate T helper cells by acting
as a co-stimulator with the antigen presenting
cell receptors.
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 Interleukin 1…

 It also helps promote the maturation and clonal

proliferation of B cells.

 IL-1 is an important part of the inflammatory

response.

 One way it mediates this is by increasing the

expression of specific cell adhesion molecules on
the endothelial cells lining the blood vessels and
thus facilitating the transmigration of immune
cells from the blood into the tissue

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 Interleukin 1…

 One very interesting action of IL-1 is its action on

the hypothalamus.

 Here IL-1, and some other cytokines (including IL-6,

the IFNs and TNFs), bind to receptors on the
endothelial cells within the hypothalamus and
appear to 'reset‘ the thermoregulatory centre,
increasing the core body temperature causing
fever.

 IL-1, therefore, has been called an "endogenous

pyrogen".
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 Interleukin 2 (IL-2)

 This cytokine was originally described as "T cell

growth factor" and is secreted primarily by T
helper cells.

 It acts on both T cells and NK cells.

 In an autocrine fashion, the antigen-primed T

helper cell secretes IL-2, stimulating itself as well
as other neighboring antigen-primed T cells, to
proliferate (T cell activation).

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 Interleukin 2 (IL-2)…

 Growing T cells in long-term culture require IL-2 as

a growth factor.

 Also, Natural Killer (NK) cell activity and CTL

activity is maximal only after cytokine help
provided by IL-2.

 This has been used as the basis of some new

cancer immunotherapies.

 IL-2, in combination with IL-4, causes activated B

cells to produce IgM and resist class switch to IgG.
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 Interleukin 4 (IL-4)

 This cytokine is released by T helper cells of the Th2 subtype and is

particularly active on resting and active B cells.

 It was originally called B cell stimulating factor.

 IL-4 increases MHC II expression on resting B cells and on

macrophages.

 On activated B cells, proliferation and differentiation is stimulated and

an antibody class switch is induced.

 A B cell stimulated with IL-4 alone becomes a plasma cell secreting IgE
and other allergy related antibodies.

 IL-4 acts with IL-10 in an immunoregulatory manner to decrease the

activity of activated macrophages
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 Interleukin 5 (IL-5)

 Like IL-4, this cytokine is secreted by the Th2 type

of T helper cell.

 In mice it also stimulates the proliferation and

differentiation of activated B cells but in humans
it does not have this effect.

 In humans IL-5 is also very important in

stimulating the growth and differentiation of
eosinophils.

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 Interleukin 6 (IL-6)

 Monocytes, macrophages and bone marrow cells secrete

this cytokine but the major producer is the Th2 type of T
helper cells.

 IL-6 acts on proliferating B cells to promote

differentiation into plasma cells and it stimulates
antibody secretion.

 Myeloid stem cells are helped to differentiate by IL-6.

 IL-6 has been described as "hepatocyte stimulating

factor" and strongly stimulates hepatocytes to make
acute phase proteins in response to inflammation.

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 Interleukin 6 (IL-6)…

 One of these acute phase proteins, C-reactive

protein, is used as a clinical indicator of
inflammation or infection.

 This cytokine also induces fever and is always

found in increased levels in sites of inflammation.

 It is very important in the regulation of the

inflammatory response.

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 Interleukin 8 (IL-8)

 IL-8 is a powerful chemotactic factor for

neutrophils and was the first identified
“chemokine”.

 Macrophages and endothelial cells secrete IL-8

when stimulated by IL-1, TNF-α or bacterial
products in order to attract neutrophils and allow
them to adhere to vascular endothelial cells.

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 Interleukin 8 (IL-8)

 This helps the neutrophils marginate on local

blood vessels and enter the tissue where they are
needed at sites of inflammation and infection.

 Neutrophils are the first line of defense against

invading bacteria.

 Look to see them in most types of infection,

especially in the early (acute) stage.

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 Interleukin 10 (IL-10)

 This interesting cytokine was originally described as "cytokine

synthesis inhibitory factor" because of its important inhibitory
role.

 It acts on macrophages to inhibit cytokine production in order

to down-regulate the Th1
type of T helper cell.

 It is released by Th2 cells and also down-regulates MHC II

expression on antigen presenting cells.

 It has been shown to act with IL-4 to decrease macrophage

inflammatory activity and may be an important cytokine in
immune regulation.
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 Interleukin 12 (IL-12)

 It is now clear that IL-12 is the major cytokine

used by antigen presenting cells to activate T
cells and drive them down the Th1 pathway.

 Secretion of IL-12 is a critical co-stimulation signal

for T cells of this pathway.

 IL-12 tends to oppose the effects of IL-4 on APC-

antigen stimulated T cells.

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 Interferon Gamma (IFN-γ)

 Activated T cells (cytotoxic and Th1) and Natural

Killer cells secrete IFN-γ.

 Its major functions are to activate macrophages

(they become angry macs) and to increase the
expression of class II MHC on APC.

 IFN- γ stimulated macrophages are more

phagocytic and they are more capable of killing
intracellular pathogens due to increased
production of H2O2, NO and lysozymes.

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 Interferon Gamma (IFN-γ)..

 They also have increased ability to present antigen.

IFN- γ secreted by Th1 cells has a down-regulatory
effect on Th2 function, and will induce a class switch to
IgG.

 It can actually inhibit development along the Th2

pathway by inducing IL-12 production by macrophages.

 This cytokine has a role in many different types of

immune responses such as delayed type
hypersensitivity, inflammation, antibody roduction and
viral infection.
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 Interferon Gamma (IFN-γ) …

 IFN-γ, along with TNF-α, is the cytokine involved

in mediating the macrophage influx seen in many
chronic infections such as tuberculosis.

 The importance of IFN-γ is evident in individuals

with deficiency of IFN-γ or of its receptor.

 In both cases overwhelming viral and

mycobacterial infection is common.

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 Tumor Necrosis Factor Alpha (TNF-α)

 Like IL-1, TNF-α is a pleotropic cytokine that has

many different effects in different circumstances,
on different cells and in conjunction with other
cytokines.

 TNF derives its name from the fact that it binds to

TNF receptors on cells (tumor cells in particular)
and activates the caspase pathway which leads
to cell death (apoptosis).

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 Tumor Necrosis Factor Alpha (TNF-α)…

 In addition to this killing effect however, TNF has

a
powerful inflammatory effect and is involved in
recruiting neutrophils monocytes, T cells and NK
cells into sites of inflammation by inducing
changes in the vascular endothelial cell adhesion
molecule profile.

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 Tumor Necrosis Factor Alpha (TNF-α)…

 Like IL-1,TNF-α has systemic effects in that it acts

on the hypothalamus to induce fever (it is also an
endogenous pyrogen).

 IFN-γ potentiates many of the effects of TNF-α

(synergy).

 However, TNF overproduction can lead to

excessive, tissuedestructive inflammation (for
example in arthritis and septic shock).

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 caspase pathway

 Caspases, or cysteine-aspartic proteases or

cysteine-dependent aspartate-directed proteases

are a family of cystein protease that play essential

roles in apoptosis (programmed cell death),

necrosis, andinflammation
 Caspases are essential in cells for apoptosi, or
programmed cell death, in development and most
other stages of adult life. and have been termed
"executioner" proteins for their roles in the cell.
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 caspase pathway

 Some caspases are also required in the immune

system for the maturation of lymhocytes.

 Failure of apoptosis is one of the main

contributions to tumour development and
autoimmune diseases; this, coupled with the
unwanted apoptosis that occurs with ischemia or
Alzheimer’s disease or, has stimulated interest in
caspases as potential therapeutic targets since
they were discovered in the mid-1990s.

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 Transforming Growth Factor beta (TGFβ)

 TGF β is secreted by platelets, macrophages and

lymphocytes.

 It has many functions which include increasing IL-1

production by activated macrophages, down-
regulating excess macrophage and T cell
activation/proliferation, inducing a class switch to
IgA by proliferating B cells and acting as a
chemoattractant for monocytes and macrophages.

 TGF β actually aids in wound healing because it

limits the inflammation caused by injury.
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Thank you!

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