'The principle role of the cell-mediated immunity is to detect and eliminate ... Results in 'systematic' disassembly of the cell. Figure 14-11: Caspase Cascade ... – PowerPoint PPT presentation
The principle role of the cell-mediated immunity is to detect and eliminate cells that harbor intracellular pathogensas well as tumor cells that have undergone genetic modification so that they present antigen not typical of normal cells (p.319)
3 Cell Organization of C-MER
Cells with direct cytotoxic activity
Antigen specific
CD8 Cytotoxic T cells (TC cells or CTLs)
Nonspecific
Natural Killer Cells (NK cells)
Macrophages
Cells that mediate the delayed-type hypersensitivity reactions (DTHR)
CD4 TH cells
TH1 cells
TH2 cells
CD8 Cytotoxic T cells (TC cells or CTLs) TH1 cells TH2 cells 4 Effector T Cells
Composed of three kinds of cells
CD8 TC cells
TH1 TH2 cells
Characterized by
Less Stringent activation requirements (Table14-1)
CD28-B7 interaction NOT necessary for activation
Increased expression of cell-adhesion molecules
2-4x increased expression of CD2 integrin LF1
Production of effector molecules (Table14-2)
Membrane-bound
Soluble
CD8 TC cells TH1 TH2 cells 5 (No Transcript) 6 Figure 10-15 7 Effector T Cells
Composed of three kinds of cells
CD8 TC cells
TH1 TH2 cells
Characterized by
Less Stringent activation requirements (Table14-1)
CD28-B7 interaction NOT necessary for activation
Increased expression of cell-adhesion molecules
2-4x increased expression of CD2 integrin LF1
Production of effector molecules (Table14-2)
Membrane-bound
Soluble
CD8 TC cells TH1 TH2 cells 8 (No Transcript) 9 Functions of T-cell Effector Molecules
Mediate target-cell destruction by TC cells
Fas ligand (membrane-bound)
perforins (soluble)
granzimes (soluble)
Promote macrophage activity
TNF-b (soluble membrane-bound)
INF-g (soluble)
GM-CSF (soluble)
Play role in B-cell activation by TH2 cells
CD40 (membrane bound)
IL-4, IL-5, IL-6 (soluble)
TC cell TH1 TH2 10 Focus Cytotoxic T cells
Generated by Immune activation of TC cell precursors
Have lytic capabilities
Play critical role in recognition of altered self cells
MHC I restricted (generally)
All nucleated cells in body express MHC I molecules
11 Generation of Effector Cytotoxic T cells
Requires three specific signals
Signals for Activation
Primary antigen specific TCR(CD8)-Ag-MHC I interaction
Co-stimulatory CD28-B7 interaction
(may not be necessary for Memory TC cell precursors )
Signals for Proliferation Differentiation
Signal from IL-2 interaction with high-affinity IL-2 Receptor
Memory TC cell precursors may produce enough IL-2 to self-proliferation
Generally TC cell precursors (CTL-Ps) need IL-2 produced from TH1 cells for proliferation
12 Figure 14-1 13 Figure 14-2 14 Figure 14-3
Attach
Four MHC I molecules bound to a specific peptide.
Biotin
Fluorescently labeled Streptavidin
MHC Tetramers bind to specific TC cell with affinity for specific Ag-MHC I chosen.
TC cell can be counted and separated by flow cytometry
sensitivity to cell populations as low as 0.1
15 Ag-MHC I complex 16 Ag-MHC I complex 17 Figure 14-4
Study demonstrated that acute infections result in varying percent distributions of Ag-MHC specific Cytotoxic T cells
(in respect to total population of TC cells in respective tissues)
Ranging from 0.6 in peripheral lymph nodes to 41 in kidneys.
18 Cytotoxic T cells Granule Mediated Homicide
1) Conjugate formation
2) Membrane attack
3) TC cell dissociation
4) Target cell obliteration (destruction)
19 Figure 14-6 20 Figure 14-5 SEM of Cytotoxic T cell-target cell conjugate 21 Cytotoxic T cells Granule Mediated Homicide
1) Conjugate formation
Recognition TCR-Ag-MHC I interaction
Embrace LFA-1 receptor (TC cell) binds to ICAMs on target cell membrane
LFA-1 is induced to a high-avidity state mediated by antigen
The LFA-1 high-avidity state regulates TC cell adhesion only to appropriate target cells displaying specific antigen.
Note The LFA-1 high-avidity state is only active for 5-10min and its deactivation may facilitate TC cell dissociation.
Brings Golgi and storage granules into closer proximity to target cell
Granule Secretion (exocytosis)
Perforin - 65kDa monomer
Undergoes conformational change upon contact with target cell membrane which exposes amphipathic domain, enabling insertion into membrane.
Once in membrane perforins polymerize and create 5-20nm pores (w/Ca2).
Granzyme
3) TC cell dissociation
4) Target cell obliteration (destruction)
24 Figure 14-9a Perforin pore formation in target cell membrane 25 Figure 14-9b EM of perforin pores in target cell membrane 26 Cytotoxic T cells Granule Mediated Homicide
1) Conjugate formation
2) Membrane attack
Cytoplasmic rearrangement
Granule Secretion (exocytosis)
Perforin - 65kDa monomer
Granzyme
Binds to mannose 6-phosphate receptor and internalized into target cell. The Perforin pores allow the Granzyme to exit internalized vesicles.
Once inside cytoplasm of target cell, initiates reaction cascade culminating in activation of endonucleases which in turn digest DNA into oligomers of 200bp (typical of apoptosis).
3) TC cell dissociation
4) Target cell obliteration (destruction)
27 Cytotoxic T cells Fas Ligand Mediated Homicide
Fas
Transmembrane protein
Member of the TNF-receptor family
Can deliver death signal when crosslinked with its natural ligand
Natural ligand is a TNF called Fas ligand (FasL)
2) FasL
Found on the membrane of TC cells
Interaction with Fas protein triggers target cell apoptosis
3) Fas-FasL interaction
elucidated by experiments with perforin KO and 1pr strain mice
Homozygous 1pr strain mice express little to no Fas
Fig 14-10 Fig 14-10 summary
28 Figure 14-10 Fas-FasL interaction experiments with KO mice 29 Figure 14-10 Fas-FasL interaction experiments with KO mice 30 Figure 14-10 Summary
Results
only two apoptotic signaling mechanism
granule mediate and Fas mediated homicide
31 Cell Death by Apoptosis
Caspase
Family of cysteine proteases which cleave after Asp residue
Normally present in cell as inactive proenzymes - procaspases
gt12 caspases with different specificity have been identified
Cleavage of procaspase produces an active initiator caspase, which in turn cleaves other caspases.
Both Granule and Fas mediated apoptotic signaling induces the caspase cascade (Fig14-11) by activating Procaspase-8.
Results in systematic disassembly of the cell
32 Figure 14-11 Caspase Cascade 33 Cell Organization of C-MER
Cells with direct cytotoxic activity
Antigen specific
CD8 Cytotoxic T cells (TC cells or CTLs)
Nonspecific
Natural Killer Cells (NK cells)
Macrophages
Cells that mediate the delayed-type hypersensitivity reactions (DTHR)
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