When cytotoxic T cells are offered a mixture of equal amounts of two target cells, one bearing a specific antigen and the other not, they kill only the target cell bearing the specific antigen. The ‘innocent bystander’ cells and the cytotoxic T cells themselves are not killed. The cytotoxic T cells are probably not killed because release of the cytotoxic effector molecules is highly polarized. As we saw in Fig. 9.38, cytotoxic T cells orient their Golgi apparatus and microtubule-organizing center to focus secretion on the point of contact with a target cell. Granule movement toward the point of contact is shown in Fig. 9.46. Cytotoxic T cells attached to several different target cells reorient their secretory apparatus toward each cell in turn and kill them one by one, strongly suggesting that the mechanism whereby cytotoxic mediators are released allows attack at only one point of contact at any one time. The narrowly focused action of CD8 cytotoxic T cells allows them to kill single infected cells in a tissue without creating widespread tissue damage (Fig. 9.47) and is of crucial importance in tissues where cell regeneration does not occur, as with the neurons of the central nervous system, or is very limited, as in the pancreatic islets.
Cytotoxic T cells can kill their targets rapidly because they store preformed cytotoxic proteins in forms that are inactive in the environment of the cytotoxic granule. Cytotoxic proteins are synthesized and loaded into the granules soon after the first encounter of a naive cytotoxic precursor T cell with its specific antigen. Ligation of the T-cell receptor similarly induces de novo synthesis of perforin and granzymes in effector CD8 T cells, so that the supply of cytotoxic granules is replenished. This makes it possible for a single CD8 T cell to kill a series of targets in succession.
Fig. 9.45 Perforin, granzymes, and serglycin are released from cytotoxic granules and deliver granzymes into the cytosol of target cells to induce apoptosis.
Release of cytochrome cinto cytosol activates apoptosis, and CAD induces DNA fragmentation Truncated BID (tBID) disrupts mitochondrial outer membrane, and activated caspase 3 cleaves ICAD, releasing caspase-activated DNase (CAD) Granzyme B is delivered into the cytosol of the infected cell via pores formed by perforin, and targets BID and pro-caspase 3 pro-caspase 3BID BAX BAD Engagement of TCR by peptide:MHC complex causes directed release of perforin and granzymes complexed with serglycin cytotoxic T cell virus-infected cell perforin cytotoxic granulegranzymeserglycin MHC TCR caspase 3 tBID cytochrome cCAD cleaved ICAD DNA