The tumor suppressor p15Ink4b regulates the differentiation and maturation of conventional dendritic cells
The tumor suppressor p15Ink4b is frequently inactivated by methylation in acute myeloid leukemia and premalignant myeloid disorders. Dendritic cells (DCs) as potent APCs play critical regulatory roles in antileukemic immune responses. In the present study, we investigated whether p15Ink4b can functi...
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| Veröffentlicht in: | Blood 2012-05, Vol.119 (21), p.5005-5015 |
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| creator | Fares, Joanna Koller, Richard Humeniuk, Rita Wolff, Linda Bies, Juraj |
| description | The tumor suppressor p15Ink4b is frequently inactivated by methylation in acute myeloid leukemia and premalignant myeloid disorders. Dendritic cells (DCs) as potent APCs play critical regulatory roles in antileukemic immune responses. In the present study, we investigated whether p15Ink4b can function as modulator of DC development. The expression of p15Ink4b is induced strongly during differentiation and activation of DCs, and its loss resulted in significant quantitative and qualitative impairments of conventional DC (cDC) development. Accordingly, ex vivo–generated BM-derived DCs from p15Ink4b-knockout mice express significantly decreased levels of the antigen-presenting (MHC II) and costimulatory (CD80 and CD86) molecules and have impaired immunostimulatory functions, such as antigen uptake and T-cell stimulation. Reexpression of p15Ink4b in progenitors restored these defects, and confirmed a positive role for p15Ink4b during cDC differentiation and maturation. Furthermore, we have shown herein that p15Ink4b expression increases phosphorylation of Erk1/Erk2 kinases, which leads to an elevated activity of the PU.1 transcription factor. In conclusion, our results establish p15Ink4b as an important modulator of cDC development and implicate a novel function for this tumor suppressor in the regulation of adaptive immune responses. |
| doi_str_mv | 10.1182/blood-2011-10-387613 |
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Dendritic cells (DCs) as potent APCs play critical regulatory roles in antileukemic immune responses. In the present study, we investigated whether p15Ink4b can function as modulator of DC development. The expression of p15Ink4b is induced strongly during differentiation and activation of DCs, and its loss resulted in significant quantitative and qualitative impairments of conventional DC (cDC) development. Accordingly, ex vivo–generated BM-derived DCs from p15Ink4b-knockout mice express significantly decreased levels of the antigen-presenting (MHC II) and costimulatory (CD80 and CD86) molecules and have impaired immunostimulatory functions, such as antigen uptake and T-cell stimulation. Reexpression of p15Ink4b in progenitors restored these defects, and confirmed a positive role for p15Ink4b during cDC differentiation and maturation. Furthermore, we have shown herein that p15Ink4b expression increases phosphorylation of Erk1/Erk2 kinases, which leads to an elevated activity of the PU.1 transcription factor. In conclusion, our results establish p15Ink4b as an important modulator of cDC development and implicate a novel function for this tumor suppressor in the regulation of adaptive immune responses.</description><identifier>ISSN: 0006-4971</identifier><identifier>ISSN: 1528-0020</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2011-10-387613</identifier><identifier>PMID: 22461492</identifier><language>eng</language><publisher>Washington, DC: Elsevier Inc</publisher><subject>Adaptive Immunity - genetics ; Animals ; Biological and medical sciences ; Bone Marrow Cells - metabolism ; Bone Marrow Cells - physiology ; Cell Differentiation - genetics ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p15 - genetics ; Cyclin-Dependent Kinase Inhibitor p15 - metabolism ; Cyclin-Dependent Kinase Inhibitor p15 - physiology ; Dendritic Cells - metabolism ; Dendritic Cells - physiology ; DNA Methylation - physiology ; Gene Deletion ; Gene Expression Regulation - immunology ; Gene Expression Regulation - physiology ; Hematologic and hematopoietic diseases ; Medical sciences ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Phagocytes, Granulocytes, and Myelopoiesis ; Promoter Regions, Genetic - physiology ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - metabolism ; Tumor Suppressor Proteins - physiology</subject><ispartof>Blood, 2012-05, Vol.119 (21), p.5005-5015</ispartof><rights>2012 American Society of Hematology</rights><rights>2015 INIST-CNRS</rights><rights>2012 by The American Society of Hematology 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-a59af6c11ededbb3f8391cb7b4f43b473f1cdf948736fd0b9e0f04f55fc9de1c3</citedby><cites>FETCH-LOGICAL-c526t-a59af6c11ededbb3f8391cb7b4f43b473f1cdf948736fd0b9e0f04f55fc9de1c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,27905,27906</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25918795$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22461492$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fares, Joanna</creatorcontrib><creatorcontrib>Koller, Richard</creatorcontrib><creatorcontrib>Humeniuk, Rita</creatorcontrib><creatorcontrib>Wolff, Linda</creatorcontrib><creatorcontrib>Bies, Juraj</creatorcontrib><title>The tumor suppressor p15Ink4b regulates the differentiation and maturation of conventional dendritic cells</title><title>Blood</title><addtitle>Blood</addtitle><description>The tumor suppressor p15Ink4b is frequently inactivated by methylation in acute myeloid leukemia and premalignant myeloid disorders. Dendritic cells (DCs) as potent APCs play critical regulatory roles in antileukemic immune responses. In the present study, we investigated whether p15Ink4b can function as modulator of DC development. The expression of p15Ink4b is induced strongly during differentiation and activation of DCs, and its loss resulted in significant quantitative and qualitative impairments of conventional DC (cDC) development. Accordingly, ex vivo–generated BM-derived DCs from p15Ink4b-knockout mice express significantly decreased levels of the antigen-presenting (MHC II) and costimulatory (CD80 and CD86) molecules and have impaired immunostimulatory functions, such as antigen uptake and T-cell stimulation. Reexpression of p15Ink4b in progenitors restored these defects, and confirmed a positive role for p15Ink4b during cDC differentiation and maturation. Furthermore, we have shown herein that p15Ink4b expression increases phosphorylation of Erk1/Erk2 kinases, which leads to an elevated activity of the PU.1 transcription factor. In conclusion, our results establish p15Ink4b as an important modulator of cDC development and implicate a novel function for this tumor suppressor in the regulation of adaptive immune responses.</description><subject>Adaptive Immunity - genetics</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Bone Marrow Cells - metabolism</subject><subject>Bone Marrow Cells - physiology</subject><subject>Cell Differentiation - genetics</subject><subject>Cells, Cultured</subject><subject>Cyclin-Dependent Kinase Inhibitor p15 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p15 - metabolism</subject><subject>Cyclin-Dependent Kinase Inhibitor p15 - physiology</subject><subject>Dendritic Cells - metabolism</subject><subject>Dendritic Cells - physiology</subject><subject>DNA Methylation - physiology</subject><subject>Gene Deletion</subject><subject>Gene Expression Regulation - immunology</subject><subject>Gene Expression Regulation - physiology</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Knockout</subject><subject>Phagocytes, Granulocytes, and Myelopoiesis</subject><subject>Promoter Regions, Genetic - physiology</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumor Suppressor Proteins - metabolism</subject><subject>Tumor Suppressor Proteins - physiology</subject><issn>0006-4971</issn><issn>1528-0020</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtv1TAQhS1ERS9t_wFC2SCxCXhiO4k3SKjiUakSm3ZtOfa4dUnsYDtX4t-TcC8tbFj5Md8cn_Eh5BXQdwB9834YY7R1QwFqoDXruxbYM7ID0fQ1pQ19TnaU0rbmsoNT8jLnB0qBs0a8IKdNw1vgstmRh5t7rMoyxVTlZZ4T5rxuZxBX4TsfqoR3y6gL5qqsnPXOYcJQvC4-hkoHW026LOlwjK4yMey3egx6rCwGm3zxpjI4jvmcnDg9Zrw4rmfk9vOnm8uv9fW3L1eXH69rI5q21FpI7VoDgBbtMDDXMwlm6AbuOBt4xxwY6yTvO9Y6SweJ1FHuhHBGWgTDzsiHg-68DBNas_pJelRz8pNOP1XUXv1bCf5e3cW9YqztJIVV4O1RIMUfC-aiJp-3EXTAuGQFQkDLOKftivIDalLMOaF7fAao2mJSv2NSW0zb1SGmte313xYfm_7ksgJvjoDORo8u6WB8fuKEhL6T4mlWXD907zGpbDwGg9YnNEXZ6P_v5Bcz_bU_</recordid><startdate>20120524</startdate><enddate>20120524</enddate><creator>Fares, Joanna</creator><creator>Koller, Richard</creator><creator>Humeniuk, Rita</creator><creator>Wolff, Linda</creator><creator>Bies, Juraj</creator><general>Elsevier Inc</general><general>Americain Society of Hematology</general><general>American Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</scope><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>7TO</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20120524</creationdate><title>The tumor suppressor p15Ink4b regulates the differentiation and maturation of conventional dendritic cells</title><author>Fares, Joanna ; Koller, Richard ; Humeniuk, Rita ; Wolff, Linda ; Bies, Juraj</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-a59af6c11ededbb3f8391cb7b4f43b473f1cdf948736fd0b9e0f04f55fc9de1c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adaptive Immunity - genetics</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Bone Marrow Cells - metabolism</topic><topic>Bone Marrow Cells - physiology</topic><topic>Cell Differentiation - genetics</topic><topic>Cells, Cultured</topic><topic>Cyclin-Dependent Kinase Inhibitor p15 - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p15 - metabolism</topic><topic>Cyclin-Dependent Kinase Inhibitor p15 - physiology</topic><topic>Dendritic Cells - metabolism</topic><topic>Dendritic Cells - physiology</topic><topic>DNA Methylation - physiology</topic><topic>Gene Deletion</topic><topic>Gene Expression Regulation - immunology</topic><topic>Gene Expression Regulation - physiology</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Knockout</topic><topic>Phagocytes, Granulocytes, and Myelopoiesis</topic><topic>Promoter Regions, Genetic - physiology</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Tumor Suppressor Proteins - metabolism</topic><topic>Tumor Suppressor Proteins - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fares, Joanna</creatorcontrib><creatorcontrib>Koller, Richard</creatorcontrib><creatorcontrib>Humeniuk, Rita</creatorcontrib><creatorcontrib>Wolff, Linda</creatorcontrib><creatorcontrib>Bies, Juraj</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fares, Joanna</au><au>Koller, Richard</au><au>Humeniuk, Rita</au><au>Wolff, Linda</au><au>Bies, Juraj</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The tumor suppressor p15Ink4b regulates the differentiation and maturation of conventional dendritic cells</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2012-05-24</date><risdate>2012</risdate><volume>119</volume><issue>21</issue><spage>5005</spage><epage>5015</epage><pages>5005-5015</pages><issn>0006-4971</issn><issn>1528-0020</issn><eissn>1528-0020</eissn><abstract>The tumor suppressor p15Ink4b is frequently inactivated by methylation in acute myeloid leukemia and premalignant myeloid disorders. Dendritic cells (DCs) as potent APCs play critical regulatory roles in antileukemic immune responses. In the present study, we investigated whether p15Ink4b can function as modulator of DC development. The expression of p15Ink4b is induced strongly during differentiation and activation of DCs, and its loss resulted in significant quantitative and qualitative impairments of conventional DC (cDC) development. Accordingly, ex vivo–generated BM-derived DCs from p15Ink4b-knockout mice express significantly decreased levels of the antigen-presenting (MHC II) and costimulatory (CD80 and CD86) molecules and have impaired immunostimulatory functions, such as antigen uptake and T-cell stimulation. Reexpression of p15Ink4b in progenitors restored these defects, and confirmed a positive role for p15Ink4b during cDC differentiation and maturation. Furthermore, we have shown herein that p15Ink4b expression increases phosphorylation of Erk1/Erk2 kinases, which leads to an elevated activity of the PU.1 transcription factor. In conclusion, our results establish p15Ink4b as an important modulator of cDC development and implicate a novel function for this tumor suppressor in the regulation of adaptive immune responses.</abstract><cop>Washington, DC</cop><pub>Elsevier Inc</pub><pmid>22461492</pmid><doi>10.1182/blood-2011-10-387613</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptive Immunity - genetics Animals Biological and medical sciences Bone Marrow Cells - metabolism Bone Marrow Cells - physiology Cell Differentiation - genetics Cells, Cultured Cyclin-Dependent Kinase Inhibitor p15 - genetics Cyclin-Dependent Kinase Inhibitor p15 - metabolism Cyclin-Dependent Kinase Inhibitor p15 - physiology Dendritic Cells - metabolism Dendritic Cells - physiology DNA Methylation - physiology Gene Deletion Gene Expression Regulation - immunology Gene Expression Regulation - physiology Hematologic and hematopoietic diseases Medical sciences Mice Mice, Inbred BALB C Mice, Knockout Phagocytes, Granulocytes, and Myelopoiesis Promoter Regions, Genetic - physiology Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Tumor Suppressor Proteins - physiology |
| title | The tumor suppressor p15Ink4b regulates the differentiation and maturation of conventional dendritic cells |
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