Effector mechanisms of cell-

mediated Immunity
PTM 3015

2016/2017

Darlington M. Mwenya
Types of cell-mediated immunity
• There are two types of cell-mediated
immune reactions designed to eliminate
different types of intracellular microbes:

– CD4+ T cells activate phagocytes to destroy

microbes residing in vesicles of these
phagocytes.

– CD8+ T cells kill any cell containing microbes

or microbial proteins in the cytoplasm.

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Cell-mediated immunity against intracellular microbes

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Induction and effector phases of cell-mediated immunity

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Migration of effector T lymphocytes
to sites of infection
• Effector T cells migrate to sites of infection
because:

– Lymphocytes express high levels of

adhesion molecules that bind to ligands
expressed on endothelium.

– Endothelial cells express such ligands

during infection.
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Migration of effector T lymphocytes to sites
of infection
• At the site of infection macrophages that
have encountered microbes express:

– TNF and IL-1, and

– Chemokines (chemoattractant
cytokines).

• Activated T lymphocytes also secrete TNF.

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Migration of effector T lymphocytes to sites
of infection

• TNF and IL-1 activate endothelial cells to

produce:

– Chemokines (chemoattractant cytokines).

– Two adhesion molecules called E-selectin

and P-selectin.

– Ligands for integrins (Ligands for LFA-1

and VLA-4 integrins).
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 Mechanisms of effector T lymphocytes
migration to sites of infection

• T lymphocyte migration involves the following

steps:

– Rolling – facilitated by adhesion molecules

called selectins.

– Adhesion – facilitated by adhesion

molecules called integrins.

– Motility – facilitated by adhesion molecules

called chemokine. 8
 Rolling

• Is facillitated by effector T lymphocytes

ligands for E-selectin, and P-selectins
expressed by endothelial cells.
• The ligand molecules bind weakly to E-
selectin and P-selectin thus permitting T
cells to roll down stream of the blood flow.

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 Adhesion
• Chemokines produced by macrophages and
endothelial cells increase the affinity of T
lymphocyte integrins for their respective
ligands.

– This results in firm binding (adhesion) of

integrins to their ligands which arrests the
rolling of T lymphocytes on endothelial
cells.

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 Motility
• Chemokines produced by macrophages
and endothelial cells

– Induce cytoskeletal changes in T

lymphocytes and increase their motility
to move outside the vessels towards the
site of infection.

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Migration of naïve and effector T lymphocytes

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Homing of T cells to site of infection
• Homing of T cells to a site of infection is
independent of antigen recognition.

• T lymphocytes that recognise microbial

antigens are:

– Activated to adhere firmly to tissue near

the infection site (or Ag) and stay long
enough to respond to microbe and
eradicate the infection.
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Migration and retention of effector T cells at sites of
infection

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Antigen-independent homing of T cells to
site of infection

• Antigen-independent homing of T cells to

site of infection:

– Allows T cells to locate the infectious

microbe for which they are specific at
any body site.

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 Effector functions of CD4+ T
lymphocytes
• TH1 lymphocytes activate macrophages to
have increased microbicidal activities that
kill the ingested microbes.

– This is the same reaction seen in the

delayed-type hypersensitivity reaction.

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 T cell-mediated macrophage
activation
• TH1 lymphocytes activate macrophages by
both:

– The CD40 ligand-CD40 interactions.

– Secreting the macrophage-activating

cytokine interferon-γ (IFN- γ).

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 T cell-mediated macrophage
activation
• Activated CD4+ T cells also secrete TNF
which facilitates homing of the leucocytes
to the site of infection.

• Activated CD8+ T cells are also able to

activate macrophages using the same
mechanisms as for CD4+ T cells.

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 Elimination of microbes by
activated macrophages
• Macrophage activation leads to the
expression of enzymes that catalyse the
production of microbicidal substances in
phagosomes and phagolysomes.

• These substances include ROI, NO, and

proteolytic enzymes.

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 Elimination of microbes by
activated macrophages
• Cell-mediated immunity is critical to host
defence in two ways:

– When macrophages are not activated by

the microbes themselves.

– When pathogenic organisms are able to

resist the defence mechanisms of the
innate immunity.
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Activation of macrophages by T lymphocytes

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 Side effects of macrophage
microbicides
• Macrophage microbicides are toxic to host
tissue e.g.:

– Injury in delayed-type hypersensitivity

e.g. Injury in tuberculin skin test.

– Injury in chronic cell-mediated immune

reaction e.g. granulomas in
mycobacterial infections.
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 Other effects of activated
macrophages
• Activated macrophage

– secrete cytokines that stimulate

recruitment of phagocyte cells and
effector T lymphocytes to the site of
infection.

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 Other effects of activated
macrophages
• Activated macrophage

– Secrete cytokines (e.g. platelet-derived

growth factor) that promotes tissue
repair.

– Amplify cell-mediated immune reaction.

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Interactions between T lymphocytes and macrophages
in cell-mediated immunity

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 Role of TH2 cells in cell-mediated
immunity
• The TH2 CD4+ lymphocytes produce IL-4,
IL-5, IL-10, and IL-13.

• IL-4 stimulates production of IgE and IL-5

activates eosinophils.

• IL-4, IL-10 and IL-13 inhibit macrophage

activation.

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Role of TH2 celles in cell-mediated
immunity
• Studies indicate that some patients
infected with Mycobacterium leprae who
have
– Well activated TH1 cells develop a less
destructive form of disease called
tuberculoid leprosy, and
– Defective TH1 activation and a dominant
TH2 response develop a more
destructive lepromatous form.
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A. TH1 and TH2 interaction

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B. TH1 and TH2 interaction

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Effector functions of CD8+ cytotoxic T
lymphocytes
• When effector CD8+ CTL encounter and
recognise a specific Ag they are activated
to release toxic granules to the area
surrounding the target cell.

• CTL granules release perforin protein

which forms a pore into the cell membrane
of the target cell.

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Effector functions of CD8+ cytotoxic T
lymphocytes
• CTL granules also release other enzymes
called granzymes which activate target-
cell enzymes called caspases.

• Activated caspases induce apoptosis.

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CD8+ CTL – mechanisms of killing infected cells

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Effector functions of CD8+ cytotoxic T
lymphocytes
• Activated CTL express a membrane
protein called Fas ligand which binds to
Fas (CD95) on target cells.

• Engangement of Fas activates caspases

and induces target cell apoptosis.

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Effector functions of CD8+ cytotoxic T
lymphocytes
• Mechanisms that cause fragmentation of
target cell DNA, may also break down
DNA of microbes living in the target cells.

• Effector functions of CD4+ T cells and

CD8+ T cells cooperate to eradicate
intracellular microbes.

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End
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Resistance of pathogenic microbes to
cell-mediated immunity
• Different microbes have evolved diverse
mechanisms to resist T lymphocyte-
mediated host defence.

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CD4+ T cells and CD8+ T cells cooperation in eradication
of intracellular microbes

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 Mechanisms of cell-mediated
resistance by pathogenic microbes
• Mechanisms by which microbes resist T
lymphocyte-mediated host defence
include:

– Inhibition of phagolysome fusion.

– Inhibition of antigen presentation.

– Inhibition of macrophage activation.

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 Mechanisms of cell-mediated
resistance by pathogenic microbes
• Mechanisms by which microbes resist T
lymphocyte-mediated host defence
include:

– Inhibition of effector cell activation.

– Killing of infected T lymphocytes.

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Evasion of cell-mediated immunity by microbes

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Evasion of cell-mediated immunity by microbes

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Evasion of cell-mediated immunity by microbes

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