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cytotoxic T cell mediated type IV DTH GPP 32


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distinguish classical DTH from cytotoxic T cell mediated DTH
classical CD4+ Th1 cells; macropahges recruited to destroty antigen
cytotoxic T cell mediated: CD8+ cytotoxic T lymphocytes kill antigen directly
5 major steps of cytotoxic T cell lymphocyte killing
antigen recognition
increased adhesion between CTL & target cell
lethal hit to target cell
recycling of CTL
death of target cell
recognition of target cell
T cell receptor in context with MHC-I moleule recognizes antigen on cell surface
adhesion between CTL and target cell
CTL has surface molecules LFA-1 and CD-2
target cell has ICAM-1 and LFA-3
LFA-1 binds ICAM-1
CD-2 binds LFA-3
on target cell
binds LFA-1 on CTL in adhesion
on CTL
binds ICAM-1 on target cell in adhesion
on CTL
binds LFA-3 on target cell in adhesion
on target cell
binds CD-2 in adhesion
2 possibilities for the lethal hit
Fas-Fas ligand
CTL excretes proteins via exocytosis
4 proteins excreted by CTL in lethal exocytosis
perforin; granzyme A & B; granulysin
what triggers the Fas-associated death domain?
accumulation of Fas molecules on target cell surface; Fas binds to Fas ligand on CTL
[lethal hit]
what is the immediate result of the Fas-associated death domain?
activation of caspase-8
[lethal hit]
activation of caspase-8 by the Fas-associated death domain leads to apoptosis
[lethal hit]
what is an important component of apoptosis in the lethal hit?
fragmentation of DNA, both of the host/target cell and of the virus
IFN-gamma and -alpha
produced by the CTL in lethal hit phase; also interferes with virus
exocytosis of proteins from CTL: main points
during lethal hit phase, protein-containing vacules are focused to site on interaction between CTL and target cell
adhesion molecules form a ring so that there is a high concentration of secreted proteins in the area of interaction
perforin creates a pore in the target cell so other proteins can enter
creates pore in target cell during exocytosis of proteins from CTL / lethal hit phase
granzyme B
acts on mitochondria by acting on BID in cytoplasm
BID associates with another molecule to create a channel through with cytochrome C can leak out of mitochondria and cause apoptosis
cytochrome C
leaks out of mitochondria, leading to apoptosis
first granzyme B must activate BID in cytoplasm; BID then interacts with another molecule to create a channel for cytochrome C leak
granzyme A
localizes to SET complex in ER during protein exocytosis phase of lethal hit
SET complex contains molecules that cause DNA breaks
SET complex
acted on by granzyme A during protein exocytosis phase of lethal hit
contains molecules that cause DNA breaks
SET complex endonuclease that causes single-stranded DNA breaks
ss DNA breaks
ds DNA breaks
SET complex exonuclease that converts ss DNA breaks to ds breaks, causing DNA fragmentation of both host cell and virus
protein exocytosed from CTL during lethal hit phase
2 forms - the smaller one punches holes in mammalian, fungal, and bacterial cells, releasing AIF
apoptosis-inducing factor released by granulysin during lethal hit phase
moves from mitochondria into nucleus to cause nuclear condensation and fragmentation
nuclear condensation and fragmentation
caused by AIF, which is released by granulysin
CTL recycling
after killing 1 target cell, CTL detaches and moves on to other target cells, w/o decrease in killing efficiency
exquisite specificity
CTL kills only cells that express antigen, in contrast to to poor sensitivity of classical DTH, in which both target cells and surrounding normal tissue are destroyed by macrophages

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