Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes
Granules containing perforin and granzymes are secreted from cytotoxic T lymphocytes. Krönke and co-workers find that acid sphingomyelase is needed for granule shrinkage just before exocytosis in this process. Granule-mediated cytotoxicity is the main effector mechanism of cytotoxic CD8 + T cells. W...
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| Veröffentlicht in: | Nature immunology 2009-07, Vol.10 (7), p.761-768 |
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| creator | Herz, Jasmin Pardo, Julian Kashkar, Hamid Schramm, Michael Kuzmenkina, Elza Bos, Erik Wiegmann, Katja Wallich, Reinhard Peters, Peter J Herzig, Stefan Schmelzer, Elmon Krönke, Martin Simon, Markus M Utermöhlen, Olaf |
| description | Granules containing perforin and granzymes are secreted from cytotoxic T lymphocytes. Krönke and co-workers find that acid sphingomyelase is needed for granule shrinkage just before exocytosis in this process.
Granule-mediated cytotoxicity is the main effector mechanism of cytotoxic CD8
+
T cells. We report that CD8
+
T cells from acid sphingomyelinase (ASMase)-deficient (ASMase-KO) mice are defective in exocytosis of cytolytic effector molecules; this defect resulted in attenuated cytotoxic activity of ASMase-KO CD8
+
T cells and delayed elimination of lymphocytic choriomeningitis virus from ASMase-KO mice. Cytolytic granules of ASMase-KO and wild-type CD8
+
T cells were equally loaded with granzymes and perforin, and correctly directed to the immunological synapse. In wild-type CD8
+
T cells, secretory granules underwent shrinkage by 82% after fusion with the plasma membrane. In ASMase-KO CD8
+
T cells, the contraction of secretory granules was markedly impaired. Thus, ASMase is required for contraction of secretory granules and expulsion of cytotoxic effector molecules. |
| doi_str_mv | 10.1038/ni.1757 |
| format | Article |
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Granule-mediated cytotoxicity is the main effector mechanism of cytotoxic CD8
+
T cells. We report that CD8
+
T cells from acid sphingomyelinase (ASMase)-deficient (ASMase-KO) mice are defective in exocytosis of cytolytic effector molecules; this defect resulted in attenuated cytotoxic activity of ASMase-KO CD8
+
T cells and delayed elimination of lymphocytic choriomeningitis virus from ASMase-KO mice. Cytolytic granules of ASMase-KO and wild-type CD8
+
T cells were equally loaded with granzymes and perforin, and correctly directed to the immunological synapse. In wild-type CD8
+
T cells, secretory granules underwent shrinkage by 82% after fusion with the plasma membrane. In ASMase-KO CD8
+
T cells, the contraction of secretory granules was markedly impaired. Thus, ASMase is required for contraction of secretory granules and expulsion of cytotoxic effector molecules.</description><identifier>ISSN: 1529-2908</identifier><identifier>EISSN: 1529-2916</identifier><identifier>DOI: 10.1038/ni.1757</identifier><identifier>PMID: 19525969</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Animals ; Arenaviridae Infections - immunology ; Arenaviridae Infections - metabolism ; Arenaviridae Infections - virology ; Biomedical and Life Sciences ; Biomedicine ; CD8-Positive T-Lymphocytes - immunology ; CD8-Positive T-Lymphocytes - metabolism ; Cell-mediated cytotoxicity ; Chemokine CCL5 - metabolism ; Cytotoxicity ; Cytotoxicity, Immunologic - immunology ; Enzymes ; Female ; Granzymes - genetics ; Granzymes - metabolism ; Hydrolases ; Immunoblotting ; Immunological Synapses - immunology ; Immunology ; Infectious Diseases ; Lymphocytes ; Lymphocytic choriomeningitis virus ; Lymphocytic choriomeningitis virus - physiology ; Male ; Mice ; Mice, Knockout ; Microscopy, Fluorescence ; Perforin - genetics ; Perforin - metabolism ; Physiological aspects ; Reverse Transcriptase Polymerase Chain Reaction ; Risk factors ; Secretory Vesicles - enzymology ; Secretory Vesicles - secretion ; Sphingomyelin Phosphodiesterase - genetics ; Sphingomyelin Phosphodiesterase - metabolism ; T cells ; T-Lymphocytes - cytology ; T-Lymphocytes - immunology ; T-Lymphocytes - metabolism ; T-Lymphocytes, Cytotoxic - cytology ; T-Lymphocytes, Cytotoxic - immunology ; T-Lymphocytes, Cytotoxic - metabolism ; Viral meningitis</subject><ispartof>Nature immunology, 2009-07, Vol.10 (7), p.761-768</ispartof><rights>Springer Nature America, Inc. 2009</rights><rights>COPYRIGHT 2009 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 2009</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c471t-1c88caf470080e84c03f8431a46efe53bad78559dffb24defdeb93f7a4c1336f3</citedby><cites>FETCH-LOGICAL-c471t-1c88caf470080e84c03f8431a46efe53bad78559dffb24defdeb93f7a4c1336f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/ni.1757$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/ni.1757$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19525969$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Herz, Jasmin</creatorcontrib><creatorcontrib>Pardo, Julian</creatorcontrib><creatorcontrib>Kashkar, Hamid</creatorcontrib><creatorcontrib>Schramm, Michael</creatorcontrib><creatorcontrib>Kuzmenkina, Elza</creatorcontrib><creatorcontrib>Bos, Erik</creatorcontrib><creatorcontrib>Wiegmann, Katja</creatorcontrib><creatorcontrib>Wallich, Reinhard</creatorcontrib><creatorcontrib>Peters, Peter J</creatorcontrib><creatorcontrib>Herzig, Stefan</creatorcontrib><creatorcontrib>Schmelzer, Elmon</creatorcontrib><creatorcontrib>Krönke, Martin</creatorcontrib><creatorcontrib>Simon, Markus M</creatorcontrib><creatorcontrib>Utermöhlen, Olaf</creatorcontrib><title>Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes</title><title>Nature immunology</title><addtitle>Nat Immunol</addtitle><addtitle>Nat Immunol</addtitle><description>Granules containing perforin and granzymes are secreted from cytotoxic T lymphocytes. Krönke and co-workers find that acid sphingomyelase is needed for granule shrinkage just before exocytosis in this process.
Granule-mediated cytotoxicity is the main effector mechanism of cytotoxic CD8
+
T cells. We report that CD8
+
T cells from acid sphingomyelinase (ASMase)-deficient (ASMase-KO) mice are defective in exocytosis of cytolytic effector molecules; this defect resulted in attenuated cytotoxic activity of ASMase-KO CD8
+
T cells and delayed elimination of lymphocytic choriomeningitis virus from ASMase-KO mice. Cytolytic granules of ASMase-KO and wild-type CD8
+
T cells were equally loaded with granzymes and perforin, and correctly directed to the immunological synapse. In wild-type CD8
+
T cells, secretory granules underwent shrinkage by 82% after fusion with the plasma membrane. In ASMase-KO CD8
+
T cells, the contraction of secretory granules was markedly impaired. Thus, ASMase is required for contraction of secretory granules and expulsion of cytotoxic effector molecules.</description><subject>Animals</subject><subject>Arenaviridae Infections - immunology</subject><subject>Arenaviridae Infections - metabolism</subject><subject>Arenaviridae Infections - virology</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>CD8-Positive T-Lymphocytes - metabolism</subject><subject>Cell-mediated cytotoxicity</subject><subject>Chemokine CCL5 - metabolism</subject><subject>Cytotoxicity</subject><subject>Cytotoxicity, Immunologic - immunology</subject><subject>Enzymes</subject><subject>Female</subject><subject>Granzymes - genetics</subject><subject>Granzymes - metabolism</subject><subject>Hydrolases</subject><subject>Immunoblotting</subject><subject>Immunological Synapses - immunology</subject><subject>Immunology</subject><subject>Infectious Diseases</subject><subject>Lymphocytes</subject><subject>Lymphocytic choriomeningitis virus</subject><subject>Lymphocytic choriomeningitis virus - physiology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Microscopy, Fluorescence</subject><subject>Perforin - genetics</subject><subject>Perforin - metabolism</subject><subject>Physiological aspects</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Risk factors</subject><subject>Secretory Vesicles - enzymology</subject><subject>Secretory Vesicles - secretion</subject><subject>Sphingomyelin Phosphodiesterase - genetics</subject><subject>Sphingomyelin Phosphodiesterase - metabolism</subject><subject>T cells</subject><subject>T-Lymphocytes - cytology</subject><subject>T-Lymphocytes - immunology</subject><subject>T-Lymphocytes - metabolism</subject><subject>T-Lymphocytes, Cytotoxic - cytology</subject><subject>T-Lymphocytes, Cytotoxic - immunology</subject><subject>T-Lymphocytes, Cytotoxic - metabolism</subject><subject>Viral meningitis</subject><issn>1529-2908</issn><issn>1529-2916</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNpt0VuL1DAUAOAgiruO4j-QoODlYcbc2qSPw-JlYUHQ9Tmm6Uk3a5uMSQvbf2-GGVxmkTwkJN85yclB6CUlG0q4-hj8hspKPkLntGLNmjW0fvxvTdQZepbzLSFUyFo8RWe0qVjV1M05-rW1vsN5d-NDH8cFBh9MBuwzNvg3LDhBPw9miglHh-0yxSneeYv7ZMI8AM5gE0w-BtwueJf8aNKCr_GwjLubWDjk5-iJM0OGF8d5hX5-_nR98XV99e3L5cX2am2FpNOaWqWscUISoggoYQl3SnBqRA0OKt6aTqqqajrnWiY6cB20DXfSCEs5rx1fobeHvLsU_8yQJz36bGEYTIA4Z81Iw4VoWIGvH8DbOKdQ3qYZY7Kgcu8KvTmg3gygfXBxSsbuM-otI6yiXNWyqM1_VBkdjN7GAM6X_ZOADycBxUxwN_Vmzllf_vh-at8drE0x5wROH_9XU6L3TdfB633Ti3x1rGhuR-ju3bHLBbw_gFyOQg_pvuSHuf4CzqmzWg</recordid><startdate>20090701</startdate><enddate>20090701</enddate><creator>Herz, Jasmin</creator><creator>Pardo, Julian</creator><creator>Kashkar, Hamid</creator><creator>Schramm, Michael</creator><creator>Kuzmenkina, Elza</creator><creator>Bos, Erik</creator><creator>Wiegmann, Katja</creator><creator>Wallich, Reinhard</creator><creator>Peters, Peter J</creator><creator>Herzig, Stefan</creator><creator>Schmelzer, Elmon</creator><creator>Krönke, Martin</creator><creator>Simon, Markus M</creator><creator>Utermöhlen, Olaf</creator><general>Nature Publishing Group US</general><general>Nature Publishing 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sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes</title><author>Herz, Jasmin ; Pardo, Julian ; Kashkar, Hamid ; Schramm, Michael ; Kuzmenkina, Elza ; Bos, Erik ; Wiegmann, Katja ; Wallich, Reinhard ; Peters, Peter J ; Herzig, Stefan ; Schmelzer, Elmon ; Krönke, Martin ; Simon, Markus M ; Utermöhlen, Olaf</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c471t-1c88caf470080e84c03f8431a46efe53bad78559dffb24defdeb93f7a4c1336f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Arenaviridae Infections - immunology</topic><topic>Arenaviridae Infections - metabolism</topic><topic>Arenaviridae Infections - virology</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>CD8-Positive T-Lymphocytes - immunology</topic><topic>CD8-Positive T-Lymphocytes - metabolism</topic><topic>Cell-mediated cytotoxicity</topic><topic>Chemokine CCL5 - metabolism</topic><topic>Cytotoxicity</topic><topic>Cytotoxicity, Immunologic - immunology</topic><topic>Enzymes</topic><topic>Female</topic><topic>Granzymes - genetics</topic><topic>Granzymes - metabolism</topic><topic>Hydrolases</topic><topic>Immunoblotting</topic><topic>Immunological Synapses - immunology</topic><topic>Immunology</topic><topic>Infectious Diseases</topic><topic>Lymphocytes</topic><topic>Lymphocytic choriomeningitis virus</topic><topic>Lymphocytic choriomeningitis virus - physiology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Microscopy, Fluorescence</topic><topic>Perforin - genetics</topic><topic>Perforin - metabolism</topic><topic>Physiological aspects</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Risk factors</topic><topic>Secretory Vesicles - enzymology</topic><topic>Secretory Vesicles - secretion</topic><topic>Sphingomyelin Phosphodiesterase - genetics</topic><topic>Sphingomyelin Phosphodiesterase - metabolism</topic><topic>T cells</topic><topic>T-Lymphocytes - cytology</topic><topic>T-Lymphocytes - immunology</topic><topic>T-Lymphocytes - metabolism</topic><topic>T-Lymphocytes, Cytotoxic - cytology</topic><topic>T-Lymphocytes, Cytotoxic - immunology</topic><topic>T-Lymphocytes, Cytotoxic - metabolism</topic><topic>Viral meningitis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Herz, Jasmin</creatorcontrib><creatorcontrib>Pardo, Julian</creatorcontrib><creatorcontrib>Kashkar, Hamid</creatorcontrib><creatorcontrib>Schramm, Michael</creatorcontrib><creatorcontrib>Kuzmenkina, Elza</creatorcontrib><creatorcontrib>Bos, Erik</creatorcontrib><creatorcontrib>Wiegmann, Katja</creatorcontrib><creatorcontrib>Wallich, Reinhard</creatorcontrib><creatorcontrib>Peters, Peter J</creatorcontrib><creatorcontrib>Herzig, Stefan</creatorcontrib><creatorcontrib>Schmelzer, Elmon</creatorcontrib><creatorcontrib>Krönke, Martin</creatorcontrib><creatorcontrib>Simon, Markus M</creatorcontrib><creatorcontrib>Utermöhlen, Olaf</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Herz, Jasmin</au><au>Pardo, Julian</au><au>Kashkar, Hamid</au><au>Schramm, Michael</au><au>Kuzmenkina, Elza</au><au>Bos, Erik</au><au>Wiegmann, Katja</au><au>Wallich, Reinhard</au><au>Peters, Peter J</au><au>Herzig, Stefan</au><au>Schmelzer, Elmon</au><au>Krönke, Martin</au><au>Simon, Markus M</au><au>Utermöhlen, Olaf</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes</atitle><jtitle>Nature immunology</jtitle><stitle>Nat Immunol</stitle><addtitle>Nat Immunol</addtitle><date>2009-07-01</date><risdate>2009</risdate><volume>10</volume><issue>7</issue><spage>761</spage><epage>768</epage><pages>761-768</pages><issn>1529-2908</issn><eissn>1529-2916</eissn><abstract>Granules containing perforin and granzymes are secreted from cytotoxic T lymphocytes. Krönke and co-workers find that acid sphingomyelase is needed for granule shrinkage just before exocytosis in this process.
Granule-mediated cytotoxicity is the main effector mechanism of cytotoxic CD8
+
T cells. We report that CD8
+
T cells from acid sphingomyelinase (ASMase)-deficient (ASMase-KO) mice are defective in exocytosis of cytolytic effector molecules; this defect resulted in attenuated cytotoxic activity of ASMase-KO CD8
+
T cells and delayed elimination of lymphocytic choriomeningitis virus from ASMase-KO mice. Cytolytic granules of ASMase-KO and wild-type CD8
+
T cells were equally loaded with granzymes and perforin, and correctly directed to the immunological synapse. In wild-type CD8
+
T cells, secretory granules underwent shrinkage by 82% after fusion with the plasma membrane. In ASMase-KO CD8
+
T cells, the contraction of secretory granules was markedly impaired. Thus, ASMase is required for contraction of secretory granules and expulsion of cytotoxic effector molecules.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>19525969</pmid><doi>10.1038/ni.1757</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Nature immunology, 2009-07, Vol.10 (7), p.761-768 |
| issn | 1529-2908 1529-2916 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_20934492 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature |
| subjects | Animals Arenaviridae Infections - immunology Arenaviridae Infections - metabolism Arenaviridae Infections - virology Biomedical and Life Sciences Biomedicine CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism Cell-mediated cytotoxicity Chemokine CCL5 - metabolism Cytotoxicity Cytotoxicity, Immunologic - immunology Enzymes Female Granzymes - genetics Granzymes - metabolism Hydrolases Immunoblotting Immunological Synapses - immunology Immunology Infectious Diseases Lymphocytes Lymphocytic choriomeningitis virus Lymphocytic choriomeningitis virus - physiology Male Mice Mice, Knockout Microscopy, Fluorescence Perforin - genetics Perforin - metabolism Physiological aspects Reverse Transcriptase Polymerase Chain Reaction Risk factors Secretory Vesicles - enzymology Secretory Vesicles - secretion Sphingomyelin Phosphodiesterase - genetics Sphingomyelin Phosphodiesterase - metabolism T cells T-Lymphocytes - cytology T-Lymphocytes - immunology T-Lymphocytes - metabolism T-Lymphocytes, Cytotoxic - cytology T-Lymphocytes, Cytotoxic - immunology T-Lymphocytes, Cytotoxic - metabolism Viral meningitis |
| title | Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes |
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