Repairing for death

The targets of cytotoxic T lymphocytes (CTLs) determine their own mode of death, say Dennis Keefe, Judy Lieberman, and colleagues (Harvard Medical School, Boston, MA). The dying cells patch themselves up so that rapid and messy necrosis is avoided in favor of a more lengthy and controlled apoptosis.The CTLs deliver their insult in the form of perforin, a pore-forming protein that helps get proteases called granzymes into the target cell. The Boston group showed that perforin addition to a target cell induced a Ca²⁺ transient and a massive plasma membrane repair response. Similar Ca²⁺-induced responses, in which lysosomal and other membranes are recruited to patch up plasma membrane holes, are known to be induced by mechanical damage to cell membranes.

Blocking the rise in Ca²⁺ and thus the repair response resulted in far more necrosis. This is presumably a consequence of breaching the plasma membrane barrier. Necrosis is induced before there is time to induce the slower process of apoptosis, which tends to sequester intracellular proteins and thus avoid unwanted autoimmune responses.

If the plasma membrane is being repaired, perforin is probably acting within endosomes to release granzymes into the cytoplasm. The Boston group gathered more evidence for this theory, but they still want to find out how perforin induces higher levels of endocytosis, and what changes within the endosome turn on perforin's pore-forming activity.

Reference: