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Surface Cathepsin B Protects Cytotoxic Lymphocytes from Self-destruction after Degranulation
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 cel...
Autores principales: | , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2002
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2196055/ https://www.ncbi.nlm.nih.gov/pubmed/12186841 http://dx.doi.org/10.1084/jem.20011836 |
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author | Balaji, Kithiganahalli N. Schaschke, Norbert Machleidt, Werner Catalfamo, Marta Henkart, Pierre A. |
author_facet | Balaji, Kithiganahalli N. Schaschke, Norbert Machleidt, Werner Catalfamo, Marta Henkart, Pierre A. |
author_sort | Balaji, Kithiganahalli N. |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-2196055 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2002 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-21960552008-04-11 Surface Cathepsin B Protects Cytotoxic Lymphocytes from Self-destruction after Degranulation Balaji, Kithiganahalli N. Schaschke, Norbert Machleidt, Werner Catalfamo, Marta Henkart, Pierre A. J Exp Med Article 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. The Rockefeller University Press 2002-08-19 /pmc/articles/PMC2196055/ /pubmed/12186841 http://dx.doi.org/10.1084/jem.20011836 Text en Copyright © 2002, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Balaji, Kithiganahalli N. Schaschke, Norbert Machleidt, Werner Catalfamo, Marta Henkart, Pierre A. Surface Cathepsin B Protects Cytotoxic Lymphocytes from Self-destruction after Degranulation |
title | Surface Cathepsin B Protects Cytotoxic Lymphocytes from Self-destruction after Degranulation |
title_full | Surface Cathepsin B Protects Cytotoxic Lymphocytes from Self-destruction after Degranulation |
title_fullStr | Surface Cathepsin B Protects Cytotoxic Lymphocytes from Self-destruction after Degranulation |
title_full_unstemmed | Surface Cathepsin B Protects Cytotoxic Lymphocytes from Self-destruction after Degranulation |
title_short | Surface Cathepsin B Protects Cytotoxic Lymphocytes from Self-destruction after Degranulation |
title_sort | surface cathepsin b protects cytotoxic lymphocytes from self-destruction after degranulation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2196055/ https://www.ncbi.nlm.nih.gov/pubmed/12186841 http://dx.doi.org/10.1084/jem.20011836 |
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