functions of th cells, th1 and th2 cells, macrophages, tc cells, and nk cells; immunoregulation
TRANSCRIPT
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Functions of Th Cells, Th1 and Th2 Cells,
Macrophages, Tc Cells, and NK Cells; Immunoregulation
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Critical Role of Th Cells in Specific Immunity
• Select effector mechanisms
• Induce proliferation in appropriate effectors
• Enhance functional activities of effectorsAPC
Thcell
B cell
Tccell
NK
AgAg
Ag
NK cell
Cytokines
GranulocyteGranulocyte MacrophageMacrophage
Cytokines
Antigen-presenting cell
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Naïve Th Cells Can Differentiate Into Th1 or Th2 Cells
ThPcell
ThOcell
Th1cell
Th2cell
ThMcell
IL-12
IL-4
IL-2 IFNγIL-2IL-4IL-5IL-10
IL-4IL-5IL-6IL-10
IL-2
IFNγIL-2
Naive Th cells Short-termstimulation
Chronicstimulation
Long termMemory cells
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Functions of Th1 and Th2 Cells
Th1cell
Th2cell
MacrophageMacrophage B cell
IFNγActivates
IL-4 IL-5
IL-10
Activates
Inhibits production
Inhibits proliferation
Mast cellMast cell EosinophilEosinophil
Antibodies (including IgE)
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Cytokines Regulate Ig Class Switching
• Fc region of antibodies determines effector function in different anatomical locations
• Class (isotype) switching produces class or subclass of antibody most effective in host defense
• Cytokines acting alone or in combination regulate class switching
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MacrophageMacrophage MacrophageMacrophage
Thcell
MacrophageMacrophage
Cytokines Lymphokines
CytokinesAnti-microbial functions
Anti-tumor functions
Activa
te
Invading agent
Antigen presentation Activated macrophage
Central Role of Macrophages in Natural and Specific Immunity
• Involved in initial defense and antigen presentation and have effector functions
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Detailed Functions of MacrophagesInflammation – Fever, Production of: IL-6, TNF-alpha, IL-1 – act as pyrogen
ImmunitySelection of lymphocytes to be activated:IL-12 results in Th1 activationIL-4 results in Th2 activationActivation of lymphocytes:Production of IL-1Processing and presentation of antigen
Reorganization of tissues,Secretion of a variety of factors:Degradative enzymes (elastase, hyaluronidase, collagenase)Fibroblast stimulation factorsStimulation of angiogenesis
Damage to tissuesHydrolases, Hydrogen peroxide productionComplement C3aTNF alpha production
Antimicrobial actionO2–dependent production of: hydrogen peroxide, superoxide, hydroxyl radical, hypochlorous acidO2-independent production of: acid hydrolases, cationic proteins, lysozyme
Anti-tumor activity produced by:Toxic factorsHydrogen peroxideComplement C3aProteases, ArginaseNitric oxideTNF alpha
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Macrophage Activation Macrophage activation results from
alterations in gene products that govern new functions.
Two major mechanisms that activate macrophages:
• IFN-γ produced by Th or Th1 cells plus bacterial endotoxin (LPS)
• IFN-γ produced by Th or Th1 cells plus TNF-α
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Mechanism of Macrophage Activation
MacrophageMacrophage ActivatedMacrophageActivatedMacrophage
Bacterial endotoxin(lipopolysaccharide)
triggers cytokine productionTh1
cell
1
IFN gamma
IFN gamma
2MacrophageMacrophage
ActivatedMacrophageActivatedMacrophage
TNF alpha
Various products
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Cytolytic T (Tc) Cells
• Tc exiting the thymus are pre-Tc cells, i.e. have TCR that can recognize antigen, but are not mature and cannot kill until “armed”
• To become armed requires two signals:1. Recognition by TCR of specific antigen
associated with class I MHC, and2. Exposure to cytokines (IL-2 and IFN-γ)
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Mechanism of Arming Tc Cells
Pre-Tc cell
Tc cell
T helper cell
Class IMHC
Class II MHCAPC
1. Cell expressing class I MHC presents antigen ( )
to a pre-Tc cell
IFNIL-2
2. Antigen-presenting cell presents antigen in
association with class II MHC to Th cell3. Th cell
makes cytokines
4. Pre-Tc celldifferentiates to
functional Tc cell
5. Tc recognizes antigen onclass I MHC-expressing target cell
6. Target cellis killed
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Features of Tc Killing
• Antigen-specific
• Requires cell-cell contact
• Each Tc capable of killing many target cells
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Main Mechanism of Tc Killing
• Tc granules contain perforin and granzymes
• Upon contact with target cell, granule contents released, perforin polymerizes and forms channel in target cell membrane
• Granzymes (serine proteases) enter target cell through channel, activate caspases and nucleases, lead to apoptosis of target cell
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Mechanism of Tc Killing
Tc cell
Ca++
Perforinmonomers
Perforinpolymerizes
Polyperforin channels
Tc cell
Target cell
Granzymes
Target cell
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Steps in Tc Killing
Tc cell1. Tc recognizes antigen ontarget cell
Target cell
Tc cell
2. A lethal hit is delivered by the Tc using agents such as perforin or granzyme B
Target cell
Tc cell
3. The Tc detaches from the target cellTarget cell
4. Target cell dies by apoptosis
Target cell
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Natural Killer (NK) Cells • Derived from bone marrow• Lack most markers for T and B cells (do not have
TCR)• Do not undergo thymic maturation• Express CD56, a specific NK marker• Express a receptor for Fc portion of IgG, called
FcRIII (CD16)• Cytokines (IL-2) promote differentiation into
lymphokine-activated killer (LAK) cells
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NK Cell Effector Mechanisms
• Mechanism of killing similar to those of Tc cells
• Not MHC-restricted
• Susceptibility of target cell to killing is inversely proportional to expression of class I MHC (killer inhibitory receptors (KIR) on NK cells recognize class I MHC and prevent killing)
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NK Effector Mechanisms(continued)
• IgG-coated target cells recognized by FcRIII (CD16) are killed by antibody-dependent cell-mediated cytotoxicity (ADCC)
• Lymphokine-activated killer cells (LAK) kill broader range of cells than do NK cells
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Regulation of Immune Responses• Magnitude determined by balance between
the extent of lymphocyte activation and tolerance induced by an antigen
• Nature determined by specificities and functional classes of lymphocytes activated
• Regulatory mechanisms may act at the recognition, activation, or effector phases of an immune response