Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells
The cytokine IL-15 is required for natural killer (NK) cell homeostasis; however, the intrinsic mechanism governing this requirement remains unexplored. Here we identify the absolute requirement for myeloid cell leukaemia sequence-1 ( Mcl1 ) in the sustained survival of NK cells in vivo . Mcl1 is hi...
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| Veröffentlicht in: | Nature communications 2014-08, Vol.5 (1), p.4539, Article 4539 |
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| creator | Sathe, Priyanka Delconte, Rebecca B. Souza-Fonseca-Guimaraes, Fernando Seillet, Cyril Chopin, Michael Vandenberg, Cassandra J. Rankin, Lucille C. Mielke, Lisa A. Vikstrom, Ingela Kolesnik, Tatiana B. Nicholson, Sandra E. Vivier, Eric Smyth, Mark J. Nutt, Stephen L. Glaser, Stefan P. Strasser, Andreas Belz, Gabrielle T. Carotta, Sebastian Huntington, Nicholas D. |
| description | The cytokine IL-15 is required for natural killer (NK) cell homeostasis; however, the intrinsic mechanism governing this requirement remains unexplored. Here we identify the absolute requirement for myeloid cell leukaemia sequence-1 (
Mcl1
) in the sustained survival of NK cells
in vivo
.
Mcl1
is highly expressed in NK cells and regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3′-UTR of
Mcl1
. Specific deletion of
Mcl1
in NK cells results in the absolute loss of NK cells from all tissues owing to a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane. This NK lymphopenia results in mice succumbing to multiorgan melanoma metastases, being permissive to allogeneic transplantation and being resistant to toxic shock following polymicrobial sepsis challenge. These results clearly demonstrate a non-redundant pathway linking IL-15 to
Mcl1
in the maintenance of NK cells and innate immune responses
in vivo
.
Mcl-1 is an important survival factor for several hematopoietic lineages including B and T lymphocytes, but its role in the Natural Killer (NK) cells has not been previously tested. Here, the authors report that deletion of Mcl-1 in the NK cell lineage leads to the loss of NK cells from all tissues. |
| doi_str_mv | 10.1038/ncomms5539 |
| format | Article |
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Mcl1
) in the sustained survival of NK cells
in vivo
.
Mcl1
is highly expressed in NK cells and regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3′-UTR of
Mcl1
. Specific deletion of
Mcl1
in NK cells results in the absolute loss of NK cells from all tissues owing to a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane. This NK lymphopenia results in mice succumbing to multiorgan melanoma metastases, being permissive to allogeneic transplantation and being resistant to toxic shock following polymicrobial sepsis challenge. These results clearly demonstrate a non-redundant pathway linking IL-15 to
Mcl1
in the maintenance of NK cells and innate immune responses
in vivo
.
Mcl-1 is an important survival factor for several hematopoietic lineages including B and T lymphocytes, but its role in the Natural Killer (NK) cells has not been previously tested. Here, the authors report that deletion of Mcl-1 in the NK cell lineage leads to the loss of NK cells from all tissues.</description><identifier>ISSN: 2041-1723</identifier><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/ncomms5539</identifier><identifier>PMID: 25119382</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/106 ; 13/2 ; 13/21 ; 14/63 ; 631/250/1619/382 ; 631/250/249 ; 631/250/262 ; 692/420/2780 ; 96/95 ; Animals ; Apoptosis - drug effects ; Apoptosis - physiology ; Cytokines - pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Female ; Gene Deletion ; Humanities and Social Sciences ; Immune System Diseases - genetics ; Immune System Diseases - physiopathology ; Immunity, Innate - genetics ; Immunity, Innate - physiology ; Interleukin-15 - pharmacology ; Interleukin-15 - physiology ; Killer Cells, Natural - drug effects ; Killer Cells, Natural - metabolism ; Killer Cells, Natural - pathology ; Lymphopenia - genetics ; Lymphopenia - pathology ; Lymphopenia - physiopathology ; Male ; Mice ; Mice, Inbred C57BL ; multidisciplinary ; Myeloid Cell Leukemia Sequence 1 Protein - genetics ; Myeloid Cell Leukemia Sequence 1 Protein - metabolism ; Science ; Science (multidisciplinary) ; Signal Transduction - physiology ; STAT5 Transcription Factor - physiology</subject><ispartof>Nature communications, 2014-08, Vol.5 (1), p.4539, Article 4539</ispartof><rights>Springer Nature Limited 2014</rights><rights>Copyright Nature Publishing Group Aug 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c453t-dbdefc3a645490713564a83030c318595df3acadf83661edd8e6280a3a99a6523</citedby><cites>FETCH-LOGICAL-c453t-dbdefc3a645490713564a83030c318595df3acadf83661edd8e6280a3a99a6523</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/ncomms5539$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://doi.org/10.1038/ncomms5539$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41096,42165,51551</link.rule.ids><linktorsrc>$$Uhttps://doi.org/10.1038/ncomms5539$$EView_record_in_Springer_Nature$$FView_record_in_$$GSpringer_Nature</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25119382$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sathe, Priyanka</creatorcontrib><creatorcontrib>Delconte, Rebecca B.</creatorcontrib><creatorcontrib>Souza-Fonseca-Guimaraes, Fernando</creatorcontrib><creatorcontrib>Seillet, Cyril</creatorcontrib><creatorcontrib>Chopin, Michael</creatorcontrib><creatorcontrib>Vandenberg, Cassandra J.</creatorcontrib><creatorcontrib>Rankin, Lucille C.</creatorcontrib><creatorcontrib>Mielke, Lisa A.</creatorcontrib><creatorcontrib>Vikstrom, Ingela</creatorcontrib><creatorcontrib>Kolesnik, Tatiana B.</creatorcontrib><creatorcontrib>Nicholson, Sandra E.</creatorcontrib><creatorcontrib>Vivier, Eric</creatorcontrib><creatorcontrib>Smyth, Mark J.</creatorcontrib><creatorcontrib>Nutt, Stephen L.</creatorcontrib><creatorcontrib>Glaser, Stefan P.</creatorcontrib><creatorcontrib>Strasser, Andreas</creatorcontrib><creatorcontrib>Belz, Gabrielle T.</creatorcontrib><creatorcontrib>Carotta, Sebastian</creatorcontrib><creatorcontrib>Huntington, Nicholas D.</creatorcontrib><title>Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><addtitle>Nat Commun</addtitle><description>The cytokine IL-15 is required for natural killer (NK) cell homeostasis; however, the intrinsic mechanism governing this requirement remains unexplored. Here we identify the absolute requirement for myeloid cell leukaemia sequence-1 (
Mcl1
) in the sustained survival of NK cells
in vivo
.
Mcl1
is highly expressed in NK cells and regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3′-UTR of
Mcl1
. Specific deletion of
Mcl1
in NK cells results in the absolute loss of NK cells from all tissues owing to a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane. This NK lymphopenia results in mice succumbing to multiorgan melanoma metastases, being permissive to allogeneic transplantation and being resistant to toxic shock following polymicrobial sepsis challenge. These results clearly demonstrate a non-redundant pathway linking IL-15 to
Mcl1
in the maintenance of NK cells and innate immune responses
in vivo
.
Mcl-1 is an important survival factor for several hematopoietic lineages including B and T lymphocytes, but its role in the Natural Killer (NK) cells has not been previously tested. Here, the authors report that deletion of Mcl-1 in the NK cell lineage leads to the loss of NK cells from all tissues.</description><subject>13/1</subject><subject>13/106</subject><subject>13/2</subject><subject>13/21</subject><subject>14/63</subject><subject>631/250/1619/382</subject><subject>631/250/249</subject><subject>631/250/262</subject><subject>692/420/2780</subject><subject>96/95</subject><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - physiology</subject><subject>Cytokines - pharmacology</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>Female</subject><subject>Gene Deletion</subject><subject>Humanities and Social Sciences</subject><subject>Immune System Diseases - genetics</subject><subject>Immune System Diseases - physiopathology</subject><subject>Immunity, Innate - genetics</subject><subject>Immunity, Innate - physiology</subject><subject>Interleukin-15 - pharmacology</subject><subject>Interleukin-15 - physiology</subject><subject>Killer Cells, Natural - drug effects</subject><subject>Killer Cells, Natural - metabolism</subject><subject>Killer Cells, Natural - pathology</subject><subject>Lymphopenia - genetics</subject><subject>Lymphopenia - pathology</subject><subject>Lymphopenia - physiopathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>multidisciplinary</subject><subject>Myeloid Cell Leukemia Sequence 1 Protein - genetics</subject><subject>Myeloid Cell Leukemia Sequence 1 Protein - metabolism</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Signal Transduction - physiology</subject><subject>STAT5 Transcription Factor - 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Sebastian</au><au>Huntington, Nicholas D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells</atitle><jtitle>Nature communications</jtitle><stitle>Nat Commun</stitle><addtitle>Nat Commun</addtitle><date>2014-08-14</date><risdate>2014</risdate><volume>5</volume><issue>1</issue><spage>4539</spage><pages>4539-</pages><artnum>4539</artnum><issn>2041-1723</issn><eissn>2041-1723</eissn><abstract>The cytokine IL-15 is required for natural killer (NK) cell homeostasis; however, the intrinsic mechanism governing this requirement remains unexplored. Here we identify the absolute requirement for myeloid cell leukaemia sequence-1 (
Mcl1
) in the sustained survival of NK cells
in vivo
.
Mcl1
is highly expressed in NK cells and regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3′-UTR of
Mcl1
. Specific deletion of
Mcl1
in NK cells results in the absolute loss of NK cells from all tissues owing to a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane. This NK lymphopenia results in mice succumbing to multiorgan melanoma metastases, being permissive to allogeneic transplantation and being resistant to toxic shock following polymicrobial sepsis challenge. These results clearly demonstrate a non-redundant pathway linking IL-15 to
Mcl1
in the maintenance of NK cells and innate immune responses
in vivo
.
Mcl-1 is an important survival factor for several hematopoietic lineages including B and T lymphocytes, but its role in the Natural Killer (NK) cells has not been previously tested. Here, the authors report that deletion of Mcl-1 in the NK cell lineage leads to the loss of NK cells from all tissues.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25119382</pmid><doi>10.1038/ncomms5539</doi><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 2041-1723 |
| ispartof | Nature communications, 2014-08, Vol.5 (1), p.4539, Article 4539 |
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| language | eng |
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| source | Springer Nature OA Free Journals |
| subjects | 13/1 13/106 13/2 13/21 14/63 631/250/1619/382 631/250/249 631/250/262 692/420/2780 96/95 Animals Apoptosis - drug effects Apoptosis - physiology Cytokines - pharmacology Disease Models, Animal Dose-Response Relationship, Drug Female Gene Deletion Humanities and Social Sciences Immune System Diseases - genetics Immune System Diseases - physiopathology Immunity, Innate - genetics Immunity, Innate - physiology Interleukin-15 - pharmacology Interleukin-15 - physiology Killer Cells, Natural - drug effects Killer Cells, Natural - metabolism Killer Cells, Natural - pathology Lymphopenia - genetics Lymphopenia - pathology Lymphopenia - physiopathology Male Mice Mice, Inbred C57BL multidisciplinary Myeloid Cell Leukemia Sequence 1 Protein - genetics Myeloid Cell Leukemia Sequence 1 Protein - metabolism Science Science (multidisciplinary) Signal Transduction - physiology STAT5 Transcription Factor - physiology |
| title | Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells |
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