Killing with Impunity

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Science  13 Sep 2002:
Vol. 297, Issue 5588, pp. 1771
DOI: 10.1126/science.297.5588.1771b

To deliver swift death to their targets, cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells secrete granules containing two classes of protein that collaborate in a lethal partnership. The first, perforin, generates polymeric channels in the target cell membrane, which kill by allowing the access of the second component, pro-apoptotic granzymes. A long-standing question about this mode of cytotoxicity has been how killer cells are able to prevent their own demise via the same mechanism.

Kithiganahalli et al. reasoned that because granule exocytosis is polarized toward the target cell-killer cell interface, protection might be mediated by a component of the secretory granule itself, possibly a membrane-associated protease. To test this idea, CTLs were induced to deploy their cytotoxic granules in the presence of inhibitors of the membrane protease cathepsin B. In this situation, CTLs from normal mice, but not those deficient in perforin, became highly susceptible to their own killing activity. Activation of CTLs led to the cell surface accumulation of an active form of cathepsin B, capable of specifically cleaving monomeric perforin. Thus, by degrading perforin before it can polymerize in their own membranes, activated killer cells prevent granzyme reentry and avoid suicide. — SJS

J. Exp. Med. 196, 493 (2002).

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