The Journal of Experimental Medicine
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Published 19 August 2002. doi:10.1084/jem.20011836
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© Rockefeller University Press, 0022-1007/2002/8/493/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 4, August 19, 2002 493-503
Surface Cathepsin B Protects Cytotoxic Lymphocytes from Self-destruction after Degranulation

Kithiganahalli N. Balaji1, Norbert Schaschke2, Werner Machleidt3, Marta Catalfamo1 and Pierre A. Henkart1

1 Experimental Immunology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892
2 Max Planck Institut fur Biochemie, 82152 Martinsried, Germany
3 Adolf Butenandt Institut fur Physiologische Chemie, Physikalische Biochemie und Zellbiologie, Ludwig Maximilians Universitat, 80336 Munich, Germany

Address correspondence to Pierre Henkart, Building 10, Room 4B36, NIH, Bethesda, MD 20892. Phone: 301-435-6404; Fax: 301-496-0887; E-mail: ph8j{at}nih.gov

The granule exocytosis cytotoxicity pathway is the major molecular mechanism for cytotoxic T lymphocyte (CTL) and natural killer (NK) cytotoxicity, but the question of how these cytotoxic lymphocytes avoid self-destruction after secreting perforin has remained unresolved. We show that CTL and NK cells die within a few hours if they are triggered to degranulate in the presence of nontoxic thiol cathepsin protease inhibitors. The potent activity of the impermeant, highly cathepsin B–specific membrane inhibitors CA074 and NS-196 strongly implicates extracellular cathepsin B. CTL suicide in the presence of cathepsin inhibitors requires the granule exocytosis cytotoxicity pathway, as it is normal with CTLs from gld mice, but does not occur in CTLs from perforin knockout mice. Flow cytometry shows that CTLs express low to undetectable levels of cathepsin B on their surface before degranulation, with a substantial rapid increase after T cell receptor triggering. Surface cathepsin B eluted from live CTL after degranulation by calcium chelation is the single chain processed form of active cathepsin B. Degranulated CTLs are surface biotinylated by the cathepsin B–specific affinity reagent NS-196, which exclusively labels immunoreactive cathepsin B. These experiments support a model in which granule-derived surface cathepsin B provides self-protection for degranulating cytotoxic lymphocytes.

Key Words: CTL • cytotoxicity • protease • granule • exocytosis


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