Transcript Effector Mechanisms of Cell

Effector Mechanisms of
Cell-Mediated Immunity
Cell Mediated Immunity
• Historically, immunologist have divided
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adaptive immunity into namely:
CMI, which can be adoptively transferred
only by viable T lymphocytes and
humoral immunity, which can be
adoptively transferred with serum
containing antibodies.
Cell Mediated Immunity
• General responses by CMI, include:
• Facilitate innate immune response to
bacteria
• Anti-viral
• Anti-fungal
• Anti-tumor
• Transplantation rejection
Cell Mediated Immunity
• Many microbes have developed
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mechanisms that enable them to survive
and even replicate within phagocytes, so
the innate immunity is unable to eradicate
infections by such microbes.
In CMI against phagocytosed microbes,
the specificity of the response is due to T
cells – but the actual effector function is
mediated by the phagocytes.
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CD4+ TH1 cells and
CD8+ T cells recognize
class II MHCassociated or class I
MHC-associated
peptide antigens of
phagocytosed
microbes, respectively,
and produce cytokines
(IFN-g, TNF) that
activate the phagocytes
to kill the microbes and
stimulate inflammation.
Listeria monocytogenes
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Protection to Listeria
infection can be
adoptively transferred
by infusing T cells
from an infected
mouse into a naïve
mouse.
This experiment was
performed in 1950 by
George Mackaness.
Delayed-type Hypersensitivity
• There is a hypersensitivity condition that
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also demonstrates the T cell activation of
macrophages.
Delayed-type hypersensitivity (DTH) is
responsible for tissue injury due to Mf and
pro-inflammatory cytokine release.
DTH will be discussed in the
hypersensitivity lectures.
DTH
Fig. 13-12
DTH
Fig. 13-13
Cell Mediated Immunity
• In a classical
sense of CMI,
CD8+ lymphocytes
kill non-phagocytic
cells infected with
microbes.
Cell Mediated Immunity
• CMI in response to helminthic parasites
is mediated by TH2 cells that stimulate
the production of IgE and activation of
eosinophils.
Cell Mediated Immunity
• Cell-mediated immune responses consist
of the development of effector T cells from
naïve cell in peripheral lymphoid organs,
migration of these effector T cells and
other leukocytes to sites of infection,
through:
• either cytokine-mediated activation of
leukocytes to destroy microbes or
• direct killing of infected cells.
Cell Mediated Immunity
• Keep in mind that naïve T cells do not
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produce effector cytokines or the
molecules to kill other cells.
The development of the effector T cells of
CMI involves the sequence of antigen
recognition, clonal expansion, and
differentiation – as we have previously
defined.
Cell Mediated Immunity
• CD4+ cells may differentiate into subsets
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of effector cells that produce distinct sets
of cytokines and therefore distinct effector
functions.
These effector cell have been previously
defined by us as TH1 and TH2.
TH1 and TH2
• The control of TH polarization is through
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the dendritic cell.
DC1 polarizes TH1 through IL-12
DC2 polarizes TH2 through IL-4
DC1 function appears to be through Tolllike receptors that bind bacterial DNA
motifs (reviewed p 282-283).
DC2 function appears to be though
increased levels of cAMP.
Toll-like receptors
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Toll-like receptors (TLRs) are a family of pattern
recognition receptors that are activated by
specific components of microbes and certain
host molecules.
INNATE RESPONOSE: They constitute the first
line of defense against many pathogens and
play a crucial role in the function of the innate
immune system.
ADAPTIVE RESPONSE: TLRs were observed to
influence the development of adaptive immune
responses, through activating antigenpresenting cells, DC1.
Toll-like receptors (TLR)
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TLRs are type I transmembrane proteins
TLR3 recognizes dsRNA, a viral product
TLR9 recognizes unmethylated CpG motifs
frequently found in the genome of bacteria and
viruses, but not vertebrates.
TLR7 recognizes small synthetic immune
modifiers including imiquimod, R-848, loxoribine,
and bropirimine, all of which are already applied
or promising for clinical use against viral
infections and cancers.
Toll-like receptors (TLR)
• Plasmacytoid dendritic cells express TLR7
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and TLR9, and respond to TLR7 and TLR9
ligands by producing a large amount of
IFN-a.
TLR3, TLR7 and TLR9 play an important
role in detecting and combating viral
infections.
TH1
vs
TH2
TH1
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TH1
The polarization to TH1 can be stimulated by
intracellular bacteria and viruses that infect
macrophages.
A second pathway already described is microbe
engagement of TLR.
A common feature of these infections is that they
elicit innate immune reactions with the
production of IL-12.
Enhancement of IL-12 production is through TH
CD40L with APC CD40.
TH1
TH1
• IL-12 binds to CD4+ cells and activates
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STAT4, a transcriptional factor that
promotes TH1 polarization.
IFN-g also induces T-bet, a transcriptional
factor that enhances the TH1 polarization.
IFN-g stimulates further production of IL-12
by APCs and IL-12r on the lymphocyte.
TH1
TH1 and TH2
TH2
• The differentiation of antigen stimulated T
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cells to TH2 is dependent on IL-4.
IL-4 activates the transcriptional factor
STAT6.
GATA-3 transcriptional factor, increases
due to antigen presentation and enhances
the transcription of TH2 cytokine gene
transcription.
Fig. 13-7
CTL-Killing
Effector Mechanisms: T-cells
• Chapter 6
• Accessory Molecules of T-cells.
• Adhesion molecules.
Integrin
• A concept has evolved suggesting that T
cells initiate antigen-independent adhesive
interactions with apposing cells to scan the
surface for specific antigen, followed by
even stronger antigen-dependent
adhesive interactions that would allow for
specific activation of T-cell proliferation,
cytokine production, or the delivery of a
lethal hit to the target cell.
Integrins
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Integrins are important for many different
physiologic processes, including
embryogenesis, thrombosis, wound healing,
tumorigenesis and immune responses.
The integrin supergene family consists of a
number of cell surface ab heterodimers.
The a and b chains are type I transmembrane
glycoproteins with a single hydrophobic
transmembrane domain, a short cytoplasmic tail,
and an extracellular domain that associates
noncovalently to form the heterodimer.
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Integrins
Integrins
• In the immune system, the most important
integrins, those of the b1, b2, and b7
subfamilies, participate in T-cell migration
and provide stimulatory signals for T-cell
proliferation and effector functions.
Integrins
• T-cell migration into tissues requires T-cell
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binding to and extravasation through
endothelium, an integrin-dependent
process.
Current models propose that chemokines
deliver the critical biochemical signals that
promote endothelial binding through the
upregulation of integrin avidity on the T
cell.
Integrins
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Integrin-mediated events are also critical for T
cells that participate in immune surveillance.
As resting T cells circulate through the blood,
they adhere specifically to the specialized
endothelium of the postcapillary venules of
secondary lymphoid organs or HEVs and
extravasate from the bloodstream into the
underlying secondary lymphoid tissues.
Integrins
• How do the adhesion molecules regulate
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their binding activity to allow both the
attachment as well as detachment
characteristics required for transmigration
into and out of the inflamed endothelium
and draining lymph nodes?
Lymphocytes have solved this problem by
tightly regulating the affinity and avidity of
integrin receptors.
Integrins
Integrins
• These conformational changes are
dependent on the presence of specific
divalent cations, which are bound by the
extracellular domains of integrins.
• Replacement of bound Ca2+ with Mg2+ for
b2 integrins or Mn2+ for b1 integrins results
in increased receptor affinity for their
ligands
Integrins