Page 561 - Veterinary Immunology, 10th Edition

triggering the release of mitochondrial cytochrome C. As described
VetBooks.ir previously, the cytochrome C generates an apoptosome that in turn

activates caspase-9 and the effector caspase cascade. The effector
caspases activate endonucleases that cause DNA fragmentation and

cell death. Cytotoxic T cells possess a granzyme inhibitor that
ensures that they are not killed during this process.
Granulysin is an antibacterial lipid-disrupting peptide found in
the granules of cytotoxic T cells and NK cells in primates and

ruminants. A related molecule (Bo-lysin) is expressed in bovine T
cells. Granulysin can kill target cells as well as a wide variety of
extracellular bacteria, fungi, and parasites. It shares homology with
other proteins that attack lipid membranes called saposins.

Saposins do not form pores but activate lipid-degrading enzymes
such as sphingomyelinases. An increase in saposins therefore
increases ceramide content, and ceramide can induce apoptosis. For
example, cytotoxic T cells can control Listeria monocytogenes and

Mycobacterium tuberculosis infections simply by killing infected cells.
It is possible that living bacteria released from these killed cells
might infect healthy cells. To avoid this, the T cell–derived
granulysin kills not only infected macrophages but also any

bacteria that happen to be inside them.
TNF-β (also called lymphotoxin-α [LT-α]) is secreted by some
cytotoxic T cells and has a similar mode of action to CD95L.
Structural changes are seen by 2 to 3 hours, and by 16 hours more

than 90% of target cells exposed to TNF-β are dead.

CD95 Pathway

The second mechanism of T cell–mediated cytotoxicity involves the
binding of a T cell surface protein called CD95L (Fas-ligand or

CD178) to a target cell death receptor called CD95 (Fas) (Fig. 18.10).
+
CD95L is expressed on activated CD8 T cells and NK cells. It binds
to CD95 on target cells. When the cells touch, CD95L binds to CD95,

and the CD95 trimerizes. This leads to the formation of a death-
inducing signaling complex (DISC) that activates initiator caspase-8
and -10. These in turn activate caspase-3 and trigger the apoptosis
cascade. The CD95L-CD95 system regulates T cell survival.
Unwanted surplus or self-reactive T cells are conveniently

561