Download Effector Mechanisms of Cell

Effector Mechanisms of
Cell-Mediated Immunity
Dr. Julia Rempel
Section of Hepatology
789-3825
[email protected]
804D JBRC
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Topics:
I. Types of Cell-Mediated Immunity
II. Migration of Effector T Lymphocytes to
Sites of Infection
III. Effector Functions of CD4+ Helper T Cells
IV. Effector Functions of CD8+ Cytoxic T Cells
V. Resistance of Pathogenic Microbes to
Cell-Mediated Immunity
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I. Types of Cell-Mediated Immunity (CMI)
Describes any adaptive response in which antigen
specific T cells have the main role. The effect can
not be transferred by serum.
Cell mediated immunity to intracellular Listeria
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II. Migration of Effector T Lymphocytes
to Sites of Infection
Immune protection: fighting off the bad guys
the way it is suppose to work
Host
Sick Monkey
Liver
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The Host
Defense
Local response
1. Innate immunity
Activated by:
- pathogen-associated molecular patterns
recognized by TLR, PRR
- viral replication
Function:
- reduce pathogen load
- direct the adaptive response.
(Innate activation, Chp 2)
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Local response
1. Innate immunity
2. Dendritic cells
Immature DC
Long lived, Slow turn over
Surveillance
-receptors (eg. TLR, PRR)
Ag acquisition
-phagocytosis
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Local response
1. Innate immunity
2. Dendritic cells
Messenger DC
afferent
lymphatics
Lymph Nodes
At Lymph Nodes
DC differentiate into mature DC
- enhance co-stimulatory molecules
- lose phagocytotic ability
Antigen presentation to naïve T cells (Chp 5).
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3. T cell and B cell
Adaptive response
The induction and effector
phases of cell-mediated
immunity (Chp 5).
Lymph Nodes
T cell Adaptive Response
T cell activation
- receives antigen information
T cell maturation
- armed effector cell not require
co-stimulation
- can act directly against infected cells
T cell expansion
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Overview of migration.
Similar to migration of
other leukocytes (Chp 2).
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Migration of naïve T Lymphocytes
LN to blood:
• Decrease
•L Selection
•CCR7
•Increase
•receptor for sphingosine
1-phosphate
L-selectin/L-selectin ligand – adhesion of naïve T cells to high
endothelial venule in lymph node
LFA-1/ICAM-1 – stable stop on HEV
CCL19/CCR7 – chemokine/chemokine receptor
- activation of intergrins and chemotaxis
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Migration of activated T Lymphocytes
Blood to Tissue:
Activated
cells
Endotheliun
(TNFα)
E- and P- selectin ligand/E- and P- selectin
- weak adhesion at infection site
sialylated carbohydrates and glycoprotein CD162
LFA-1 or VLA-1/ICAM-1 or VCAM-1
CXCL10/CXCR3
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- stable stop
- activation of integrins and chemotaxis
Migration and retention
of effector T cells at sites
of infection
At infection site
macrophage and
endothelial cell release
chemokines
Retention:
Antigen
dependent
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Migration:
Antigen
independent
Innate response
Clean up the mess
Rebuild
Return to homeostasis
Lymph Nodes
T cell Adaptive response
Store info for future conflict
Shut down (die off)
avoid becoming the enemy 13OC11
Healthy Monkey
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III. Effector Functions of CD4+ Helper T Lymphocytes
A. Cell-mediated Macrophage Activation against Intracellular Microbes
1. Effector CD4 T cells (TH1) activate the macrophages
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2. Activation of naïve CD4 T cells
Abbas & Lichtman, 2008
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B. Role of Th1/Th2 Cells in Cell-Mediated Immunity
The balance between TH1 and TH2 cell activation
determines outcome of intracellular infections
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C. Regulatory T cells:
(Chapter 9 - Immunological Tolerance and Autoimmunity)
Disease
Autoimmune
disease
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Treg
absence
Treg
presence
Autoimmunity
Homeostasis
HCV infection
Infection
clearance
Chronic infection
Immune outcome
Homeostasis ☺
Pathology D. CD8 T cell activation and survival
CD4 cell help required for CD8 cell activation
CD8 cells are harder to activate naïve CD4 cells
- Macrophages can activate naïve CD4 cells, but not CD8 cells
- DC have a harder time activating naïve CD8 cells
DC need to be appropriately activated first:
- infection, upregulation of co-stimulatory receptors
- CD4 cell bound to same DC as the CD8 cells
CD4
CD8
TCR:MHCpeptide
DC
Examples:
• HIV-specific CD8 T cells – although viable, are not
cytolytic or produce cytokines.
• Chronic LCMV infection in CD4-/- mice, CD8 T cells
proliferate but no killing.
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IV.
Effector Functions of CD8+ Cytotoxic T Lymphocytes
A. Ag-mediated Cytotoxicity
defense against infected cells (viruses, cytoplasmic bacteria, some
protozoan Toxoplasma gondii)
tumor cells
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Mechanisms of killing of infected cells by
CD8+ cytotoxic T lymphocytes
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- granules:
initially formed when naïve CD8 T cell is primed
replenished upon subsequent interaction
preformed granules - quick release at synapse
inactive in CTL
- granules contain:
perforin
polymerizes, forming transmembrane pores through target cell membranes.
the pores are cylindrical – lipophilic outside, hydrophobic inside.
allows water and salt (granzymes) to get into cell quickly.
perforin on own is inefficient in killing.
granzymes – three+ proteases, digestive enzymes
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Granzyme B
cleaves pro-enzyme caspase 3 to active caspase 3
Caspase-3
degrades inhibitor of CAD (ICAD),
bound to caspase-3-activated deoxyribonuclease (CAD)
CAD is a endonuclease,
degrades double stranded DNA (200-bp),
responsible for DNA fragmentation that results in
chromatin condensation.
TUNEL assay.
Granzyme B may degrade ICAD directly and caspases
amply affect.
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Granzyme B
pro-Caspase 3
ICAD
CAD
B. Fas-mediated apoptosis:
- Killing of tumor cells/macrophage infected cells
T cell FasL:Fas tumor cell
- Quenching an immune response
T cell FasL:Fas T cell
- Tumor killing of T cells
Tumor cell FasL: Fas T cell
Nature Medicine 6, 493 - 495 (2000)
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C. CD8 cell cytokine production
IFN-γ – inhibits certain viral replication directly
enhances - MHC class I and class II
- adhesion and co-stimulatory molecules
- Ag presenting capacity of macrophages
TNF-α – synergies with IFN-γ
macrophage responses
anti-viral
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Cooperation between CD4+ and CD8+ cells in the
eradication of intracellular infections
Abbas & Lichtman, 2008
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V.
Resistance of Pathogenic Microbes to Cell-Mediated
Immunity
Factors in Infection Outcome
Viral Pathology
Outcome
Immune
Protection
Immunopathology
Viral induction of immunopathogenesis
Martial Arts – use your enemies strengths as their weakness.
Pathogens use host immune systems to harm the host.
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Types of Infection Outcomes
1. Protection with limited viral or immunopathology
Viral Pathology
Viral genetics
Host Factors
Immune System
Induction
Protection
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Immunopathology
2. Protection with considerable immunopathology
Viral Pathology
Induction
Protection
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Immunopathology
3. Limited protection, considerable immunopathology
Viral Pathology
Induction
Deregulation
1. Evasion
Protection
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2. Immunopathology
Evasion of cell-mediated immunity by microbes
1. Inhibition of lysosome digestion
Abbas & Lichtman, 2008
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Evasion of cell-mediated immunity by microbes
2. Inhibition of antigen presentation
Abbas & Lichtman, 2008
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Evasion of cell-mediated immunity by microbes
3. Cytokine deregulation
- Chronic hepatitis B infection vs. resolved HBV infection
high frequency of circulating CD4CD25Foxp3 Tregs
Tregs correlated serum HBV DNA levels.
Abbas & Lichtman, 2008
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4. Latency (hiding)
genetic function of virus
eg. Herpesvirus: cytomegalovirus, EBV, herpes simplex virus
5. Antigenic escape (the disguise)
- RNA viruses – high mutation rate, error prone polymerase
Hepatitis C Virus
- Reverse Transcriptase – higher mutation rate
Lentivirus, HIV
Polymerase
Genome
Rate/nucleotide
Mutations/virus
DNA
100 kb
1/105-1011
<1
RNA
RT
10 kb
10 kb
1/103-104
<1/103
>1
1-10
• Reverse Transcriptase – highly error prone
• DNA polymerases – proof reading functions
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6.
Antigenic shift (specialized disguise)
- is the process by which two different strains of influenza combine to
form a new subtype having a mixture of the surface antigens of the two
original strains: Hemagglutinin (H) and Neruaminidase (N)
- only occurs in influenza A, infects humans, birds, swine, horses, dogs
H1N2
H5N2
+
H5N1
Note: antigenic drift – natural mutation overtime which could lead to viral escape.
reassortment or viral shift - other viral systems or experimentally induced
modified http://en.wikipedia.org/wiki/reassortment
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Topics:
I.
II.
III.
IV.
V.
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Types of Cell-Mediated Immunity
Migration of Effector T Lymphocytes to
Sites of Infection
Effector Functions of CD4+ Helper T Cells
Effector Functions of CD8+ Cytoxic T Cells
Resistance of Pathogenic Microbes to
Cell-Mediated Immunity