Apoptotic Pathways Are Selectively Activated by Granzyme A and/or Granzyme B in CTL-Mediated Target Cell Lysis
Purified cytolytic T lymphocyte (CTL) proteases granzyme (gzm)A and gzmB with sublytic dose of perforin (perf) initiate distinct proapoptotic pathways. Their physiological relevance in CTL-mediated target cell apoptosis is elusive. Using ex vivo virus-immune CD8+T cells from mice deficient in perf,...
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| Veröffentlicht in: | The Journal of cell biology 2004-11, Vol.167 (3), p.457-468 |
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| container_title | The Journal of cell biology |
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| creator | Pardo, Julián Bosque, Alberto Brehm, Reina Wallich, Reinhard Naval, Javier Müllbacher, Arno Anel, Alberto Simon, Markus M. |
| description | Purified cytolytic T lymphocyte (CTL) proteases granzyme (gzm)A and gzmB with sublytic dose of perforin (perf) initiate distinct proapoptotic pathways. Their physiological relevance in CTL-mediated target cell apoptosis is elusive. Using ex vivo virus-immune CD8+T cells from mice deficient in perf, gzmA and/or gzmB, and the Fas-resistant EL4.F15 tumor target cell, we show that (a) CTL from gzmA-/-or gzmB-/-mice similarly induced early proapoptotic features, such as phosphatidyl serine (PS) exposure on plasma membrane, Δ Ψmloss, and reactive oxygen radical generation, though with distinct kinetics; (b) CTL from gzmA-/-but not from gzmB-/-mice activate caspase 3 and 9; (c) PS exposure induced by CTL from gzmA-/-or gzmB-/-mice is prevented, respectively, by caspase inhibitors or by reactive oxygen scavengers without interfering with target cell death; and (d) all gzm-induced apoptotic features analyzed depend critically on perf. Thus, perf is the principal regulator in CTL-mediated and gzm-facilitated intracellular processes. The ability of gzmA and gzmB to induce multiple independent cell death pathways may be the hosts response to circumvent evasion strategies of pathogens and tumors. |
| doi_str_mv | 10.1083/jcb.200406115 |
| format | Article |
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Their physiological relevance in CTL-mediated target cell apoptosis is elusive. Using ex vivo virus-immune CD8+T cells from mice deficient in perf, gzmA and/or gzmB, and the Fas-resistant EL4.F15 tumor target cell, we show that (a) CTL from gzmA-/-or gzmB-/-mice similarly induced early proapoptotic features, such as phosphatidyl serine (PS) exposure on plasma membrane, Δ Ψmloss, and reactive oxygen radical generation, though with distinct kinetics; (b) CTL from gzmA-/-but not from gzmB-/-mice activate caspase 3 and 9; (c) PS exposure induced by CTL from gzmA-/-or gzmB-/-mice is prevented, respectively, by caspase inhibitors or by reactive oxygen scavengers without interfering with target cell death; and (d) all gzm-induced apoptotic features analyzed depend critically on perf. Thus, perf is the principal regulator in CTL-mediated and gzm-facilitated intracellular processes. 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The ability of gzmA and gzmB to induce multiple independent cell death pathways may be the hosts response to circumvent evasion strategies of pathogens and tumors.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - immunology</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Cell lines</subject><subject>Cell membranes</subject><subject>Cells</subject><subject>Cells, Cultured</subject><subject>Cellular biology</subject><subject>Cultured cells</subject><subject>Cytolysis</subject><subject>Cytotoxicity, Immunologic</subject><subject>Granzymes</subject><subject>Kinetics</subject><subject>Membrane Glycoproteins - physiology</subject><subject>Membrane Potentials</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Pathogens</subject><subject>Perforin</subject><subject>Phosphatidylserines - metabolism</subject><subject>Pore Forming Cytotoxic Proteins</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Serine Endopeptidases - deficiency</subject><subject>Serine Endopeptidases - physiology</subject><subject>T lymphocytes</subject><subject>T-Lymphocytes, Cytotoxic - enzymology</subject><subject>T-Lymphocytes, Cytotoxic - immunology</subject><subject>Time Factors</subject><subject>Tumors</subject><subject>Viruses</subject><issn>0021-9525</issn><issn>1540-8140</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1rGzEQxUVoaZy0x9xKET3ktok-Le2lsDFNUnBIoe5ZaLVSIrNeuZKcsv3rI8cmbnsazcyPxxs9AM4wusBI0sulaS8IQgxNMeZHYII5Q5XEDL0BE4QIrmpO-DE4SWmJCiYYfQeOMeeUlXYChmYd1jlkb-B3nR9_6zHBJlr4w_bWZP9k-xE224fOtoPtCG-iHv6MKwsbqIfuMsTD5Ar6Ac4W8-rOdv6FX-j4YDOc2b6H8zH59B68dbpP9sO-noKf118Xs9tqfn_zbdbMK8NqkYt_gRzBlLNOttrQ1hHkura1VCIiasEFN45LYpxBTkpKESZG1sxNuXCEt_QUfNnprjftynbGDjnqXq2jX-k4qqC9-ncz-Ef1EJ4UwYIwyYrA-V4ghl8bm7Ja-WTKHXqwYZPUVJQPl7Iu4Of_wGXYxKEct9VCkteMFKjaQSaGlKJ1r04wUtsYVYlRvcZY-E9_2z_Q-9wK8HEHLFMO8bCfEkIL8wxerKGQ</recordid><startdate>20041108</startdate><enddate>20041108</enddate><creator>Pardo, Julián</creator><creator>Bosque, Alberto</creator><creator>Brehm, Reina</creator><creator>Wallich, Reinhard</creator><creator>Naval, Javier</creator><creator>Müllbacher, Arno</creator><creator>Anel, Alberto</creator><creator>Simon, Markus M.</creator><general>Rockefeller University Press</general><general>The Rockefeller University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20041108</creationdate><title>Apoptotic Pathways Are Selectively Activated by Granzyme A and/or Granzyme B in CTL-Mediated Target Cell Lysis</title><author>Pardo, Julián ; 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Their physiological relevance in CTL-mediated target cell apoptosis is elusive. Using ex vivo virus-immune CD8+T cells from mice deficient in perf, gzmA and/or gzmB, and the Fas-resistant EL4.F15 tumor target cell, we show that (a) CTL from gzmA-/-or gzmB-/-mice similarly induced early proapoptotic features, such as phosphatidyl serine (PS) exposure on plasma membrane, Δ Ψmloss, and reactive oxygen radical generation, though with distinct kinetics; (b) CTL from gzmA-/-but not from gzmB-/-mice activate caspase 3 and 9; (c) PS exposure induced by CTL from gzmA-/-or gzmB-/-mice is prevented, respectively, by caspase inhibitors or by reactive oxygen scavengers without interfering with target cell death; and (d) all gzm-induced apoptotic features analyzed depend critically on perf. Thus, perf is the principal regulator in CTL-mediated and gzm-facilitated intracellular processes. The ability of gzmA and gzmB to induce multiple independent cell death pathways may be the hosts response to circumvent evasion strategies of pathogens and tumors.</abstract><cop>United States</cop><pub>Rockefeller University Press</pub><pmid>15534000</pmid><doi>10.1083/jcb.200406115</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis Apoptosis - immunology Cell death Cell Line, Tumor Cell lines Cell membranes Cells Cells, Cultured Cellular biology Cultured cells Cytolysis Cytotoxicity, Immunologic Granzymes Kinetics Membrane Glycoproteins - physiology Membrane Potentials Mice Mice, Knockout Pathogens Perforin Phosphatidylserines - metabolism Pore Forming Cytotoxic Proteins Reactive Oxygen Species - metabolism Serine Endopeptidases - deficiency Serine Endopeptidases - physiology T lymphocytes T-Lymphocytes, Cytotoxic - enzymology T-Lymphocytes, Cytotoxic - immunology Time Factors Tumors Viruses |
| title | Apoptotic Pathways Are Selectively Activated by Granzyme A and/or Granzyme B in CTL-Mediated Target Cell Lysis |
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