Cholesterol negatively regulates IL-9-producing CD8 + T cell differentiation and antitumor activity
CD8 T cells can be polarized into IL-9-secreting (Tc9) cells. We previously showed that adoptive therapy using tumor-specific Tc9 cells generated stronger antitumor responses in mouse melanoma than classical Tc1 cells. To understand why Tc9 cells exert stronger antitumor responses, we used gene prof...
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| Veröffentlicht in: | The Journal of experimental medicine 2018-06, Vol.215 (6), p.1555-1569 |
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| container_title | The Journal of experimental medicine |
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| creator | Ma, Xingzhe Bi, Enguang Huang, Chunjian Lu, Yong Xue, Gang Guo, Xing Wang, Aibo Yang, Maojie Qian, Jianfei Dong, Chen Yi, Qing |
| description | CD8
T cells can be polarized into IL-9-secreting (Tc9) cells. We previously showed that adoptive therapy using tumor-specific Tc9 cells generated stronger antitumor responses in mouse melanoma than classical Tc1 cells. To understand why Tc9 cells exert stronger antitumor responses, we used gene profiling to compare Tc9 and Tc1 cells. Tc9 cells expressed different levels of cholesterol synthesis and efflux genes and possessed significantly lower cholesterol content than Tc1 cells. Unique to Tc9, but not other CD8
or CD4
T cell subsets, manipulating cholesterol content in polarizing Tc9 cells significantly affected IL-9 expression and Tc9 differentiation and antitumor response in vivo. Mechanistic studies showed that IL-9 was indispensable for Tc9 cell persistence and antitumor effects, and cholesterol or its derivatives inhibited IL-9 expression by activating liver X receptors (LXRs), leading to LXR Sumoylation and reduced p65 binding to
promoter. Our study identifies cholesterol as a critical regulator of Tc9 cell differentiation and function. |
| doi_str_mv | 10.1084/jem.20171576 |
| format | Article |
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T cells can be polarized into IL-9-secreting (Tc9) cells. We previously showed that adoptive therapy using tumor-specific Tc9 cells generated stronger antitumor responses in mouse melanoma than classical Tc1 cells. To understand why Tc9 cells exert stronger antitumor responses, we used gene profiling to compare Tc9 and Tc1 cells. Tc9 cells expressed different levels of cholesterol synthesis and efflux genes and possessed significantly lower cholesterol content than Tc1 cells. Unique to Tc9, but not other CD8
or CD4
T cell subsets, manipulating cholesterol content in polarizing Tc9 cells significantly affected IL-9 expression and Tc9 differentiation and antitumor response in vivo. Mechanistic studies showed that IL-9 was indispensable for Tc9 cell persistence and antitumor effects, and cholesterol or its derivatives inhibited IL-9 expression by activating liver X receptors (LXRs), leading to LXR Sumoylation and reduced p65 binding to
promoter. Our study identifies cholesterol as a critical regulator of Tc9 cell differentiation and function.</description><identifier>ISSN: 0022-1007</identifier><identifier>EISSN: 1540-9538</identifier><identifier>DOI: 10.1084/jem.20171576</identifier><identifier>PMID: 29743292</identifier><language>eng</language><publisher>United States: Rockefeller University Press</publisher><subject>Anticancer properties ; Antitumor activity ; CD4 antigen ; CD8 antigen ; Cell differentiation ; Cholesterol ; Differentiation (biology) ; Efflux ; In vivo methods and tests ; Interleukin 9 ; Liver ; Liver X receptors ; Lymphocytes ; Lymphocytes T ; Melanoma ; Receptors ; SUMO protein</subject><ispartof>The Journal of experimental medicine, 2018-06, Vol.215 (6), p.1555-1569</ispartof><rights>2018 Ma et al.</rights><rights>Copyright Rockefeller University Press Jun 4, 2018</rights><rights>2018 Ma et al. 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-cc01695d2f4124500f7fdad49d0363b64409ac0264df3fd45b621173d68f95d3</citedby><cites>FETCH-LOGICAL-c412t-cc01695d2f4124500f7fdad49d0363b64409ac0264df3fd45b621173d68f95d3</cites><orcidid>0000-0002-0084-9130 ; 0000-0002-0532-160X ; 0000-0003-1529-3398 ; 0000-0003-4763-4409</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29743292$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ma, Xingzhe</creatorcontrib><creatorcontrib>Bi, Enguang</creatorcontrib><creatorcontrib>Huang, Chunjian</creatorcontrib><creatorcontrib>Lu, Yong</creatorcontrib><creatorcontrib>Xue, Gang</creatorcontrib><creatorcontrib>Guo, Xing</creatorcontrib><creatorcontrib>Wang, Aibo</creatorcontrib><creatorcontrib>Yang, Maojie</creatorcontrib><creatorcontrib>Qian, Jianfei</creatorcontrib><creatorcontrib>Dong, Chen</creatorcontrib><creatorcontrib>Yi, Qing</creatorcontrib><title>Cholesterol negatively regulates IL-9-producing CD8 + T cell differentiation and antitumor activity</title><title>The Journal of experimental medicine</title><addtitle>J Exp Med</addtitle><description>CD8
T cells can be polarized into IL-9-secreting (Tc9) cells. We previously showed that adoptive therapy using tumor-specific Tc9 cells generated stronger antitumor responses in mouse melanoma than classical Tc1 cells. To understand why Tc9 cells exert stronger antitumor responses, we used gene profiling to compare Tc9 and Tc1 cells. Tc9 cells expressed different levels of cholesterol synthesis and efflux genes and possessed significantly lower cholesterol content than Tc1 cells. Unique to Tc9, but not other CD8
or CD4
T cell subsets, manipulating cholesterol content in polarizing Tc9 cells significantly affected IL-9 expression and Tc9 differentiation and antitumor response in vivo. Mechanistic studies showed that IL-9 was indispensable for Tc9 cell persistence and antitumor effects, and cholesterol or its derivatives inhibited IL-9 expression by activating liver X receptors (LXRs), leading to LXR Sumoylation and reduced p65 binding to
promoter. Our study identifies cholesterol as a critical regulator of Tc9 cell differentiation and function.</description><subject>Anticancer properties</subject><subject>Antitumor activity</subject><subject>CD4 antigen</subject><subject>CD8 antigen</subject><subject>Cell differentiation</subject><subject>Cholesterol</subject><subject>Differentiation (biology)</subject><subject>Efflux</subject><subject>In vivo methods and tests</subject><subject>Interleukin 9</subject><subject>Liver</subject><subject>Liver X receptors</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Melanoma</subject><subject>Receptors</subject><subject>SUMO protein</subject><issn>0022-1007</issn><issn>1540-9538</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNpdkcuLFDEQxoMo7uzqzbMEvAjaa-XduSzIuOrCgJe5h0wesxm6O2PSvTD_vVn2gXoIRahffdRXH0LvCFwS6PmXQxgvKRBFhJIv0IoIDp0WrH-JVgCUdgRAnaHzWg8AhHMhX6MzqhVnVNMVcuvbPIQ6h5IHPIW9ndNdGE64hP0y2DlUfLPpdHcs2S8uTXu8_tbjT3iLXRgG7FOMoYRpTm0uT9hOvr05zcuYC7auiaX59Aa9inao4e1jvUDb79fb9c9u8-vHzfrrpnOc0LlzDojUwtPYvlwARBW99Vx7YJLtJOegrQMquY8sei52khKimJd9bGPsAl09yB6X3Ri8a2sVO5hjSaMtJ5NtMv92pnRr9vnOCN0rTXQT-PgoUPLvpR3FjKne-7RTyEs1FJgCITljDf3wH3rIS5mau0ZxLYRSvWjU5wfKlVxrCfF5GQLmPjzTwjNP4TX8_d8GnuGntNgfsjGVeQ</recordid><startdate>20180604</startdate><enddate>20180604</enddate><creator>Ma, Xingzhe</creator><creator>Bi, Enguang</creator><creator>Huang, Chunjian</creator><creator>Lu, Yong</creator><creator>Xue, Gang</creator><creator>Guo, Xing</creator><creator>Wang, Aibo</creator><creator>Yang, Maojie</creator><creator>Qian, Jianfei</creator><creator>Dong, Chen</creator><creator>Yi, Qing</creator><general>Rockefeller University Press</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7T5</scope><scope>7TK</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><orcidid>https://orcid.org/0000-0002-0084-9130</orcidid><orcidid>https://orcid.org/0000-0002-0532-160X</orcidid><orcidid>https://orcid.org/0000-0003-1529-3398</orcidid><orcidid>https://orcid.org/0000-0003-4763-4409</orcidid></search><sort><creationdate>20180604</creationdate><title>Cholesterol negatively regulates IL-9-producing CD8 + T cell differentiation and antitumor activity</title><author>Ma, Xingzhe ; 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T cells can be polarized into IL-9-secreting (Tc9) cells. We previously showed that adoptive therapy using tumor-specific Tc9 cells generated stronger antitumor responses in mouse melanoma than classical Tc1 cells. To understand why Tc9 cells exert stronger antitumor responses, we used gene profiling to compare Tc9 and Tc1 cells. Tc9 cells expressed different levels of cholesterol synthesis and efflux genes and possessed significantly lower cholesterol content than Tc1 cells. Unique to Tc9, but not other CD8
or CD4
T cell subsets, manipulating cholesterol content in polarizing Tc9 cells significantly affected IL-9 expression and Tc9 differentiation and antitumor response in vivo. Mechanistic studies showed that IL-9 was indispensable for Tc9 cell persistence and antitumor effects, and cholesterol or its derivatives inhibited IL-9 expression by activating liver X receptors (LXRs), leading to LXR Sumoylation and reduced p65 binding to
promoter. Our study identifies cholesterol as a critical regulator of Tc9 cell differentiation and function.</abstract><cop>United States</cop><pub>Rockefeller University Press</pub><pmid>29743292</pmid><doi>10.1084/jem.20171576</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-0084-9130</orcidid><orcidid>https://orcid.org/0000-0002-0532-160X</orcidid><orcidid>https://orcid.org/0000-0003-1529-3398</orcidid><orcidid>https://orcid.org/0000-0003-4763-4409</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Anticancer properties Antitumor activity CD4 antigen CD8 antigen Cell differentiation Cholesterol Differentiation (biology) Efflux In vivo methods and tests Interleukin 9 Liver Liver X receptors Lymphocytes Lymphocytes T Melanoma Receptors SUMO protein |
| title | Cholesterol negatively regulates IL-9-producing CD8 + T cell differentiation and antitumor activity |
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