Circulating IL-15 exists as heterodimeric complex with soluble IL-15Rα in human and mouse serum
IL-15 is an important cytokine for the function of the immune system, but the form(s) of IL-15 produced in the human body are not fully characterized. Coexpression of the single-chain IL-15 and the IL-15 receptor alpha (IL-15Rα) in the same cell allows for efficient production, surface display, and...
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| Veröffentlicht in: | Blood 2012-07, Vol.120 (1), p.e1-e8 |
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| creator | Bergamaschi, Cristina Bear, Jenifer Rosati, Margherita Beach, Rachel Kelly Alicea, Candido Sowder, Raymond Chertova, Elena Rosenberg, Steven A. Felber, Barbara K. Pavlakis, George N. |
| description | IL-15 is an important cytokine for the function of the immune system, but the form(s) of IL-15 produced in the human body are not fully characterized. Coexpression of the single-chain IL-15 and the IL-15 receptor alpha (IL-15Rα) in the same cell allows for efficient production, surface display, and eventual cleavage and secretion of the bioactive IL-15/IL-15Rα heterodimer in vivo, whereas the single-chain IL-15 is poorly secreted and unstable. This observation led to the hypothesis that IL-15 is produced and secreted only as a heterodimer with IL-15Rα. We purified human IL-15/IL-15Rα complexes from overproducing human cell lines and developed an ELISA specifically measuring the heterodimeric form of IL-15. Analysis of sera from melanoma patients after lymphodepletion revealed the presence of circulating IL-15/IL-15Rα complexes in amounts similar to the total IL-15 quantified by a commercial IL-15 ELISA that detects both the single-chain and the heterodimeric forms of the cytokine. Therefore, in lymphodepleted cancer patients, the serum IL-15 is exclusively present in its heterodimeric form. Analysis of the form of IL-15 present in either normal or lymphodepleted mice agrees with the human data. These results have important implications for development of assays and materials for clinical applications of IL-15. |
| doi_str_mv | 10.1182/blood-2011-10-384362 |
| format | Article |
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Coexpression of the single-chain IL-15 and the IL-15 receptor alpha (IL-15Rα) in the same cell allows for efficient production, surface display, and eventual cleavage and secretion of the bioactive IL-15/IL-15Rα heterodimer in vivo, whereas the single-chain IL-15 is poorly secreted and unstable. This observation led to the hypothesis that IL-15 is produced and secreted only as a heterodimer with IL-15Rα. We purified human IL-15/IL-15Rα complexes from overproducing human cell lines and developed an ELISA specifically measuring the heterodimeric form of IL-15. Analysis of sera from melanoma patients after lymphodepletion revealed the presence of circulating IL-15/IL-15Rα complexes in amounts similar to the total IL-15 quantified by a commercial IL-15 ELISA that detects both the single-chain and the heterodimeric forms of the cytokine. Therefore, in lymphodepleted cancer patients, the serum IL-15 is exclusively present in its heterodimeric form. Analysis of the form of IL-15 present in either normal or lymphodepleted mice agrees with the human data. These results have important implications for development of assays and materials for clinical applications of IL-15.</description><identifier>ISSN: 0006-4971</identifier><identifier>ISSN: 1528-0020</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2011-10-384362</identifier><identifier>PMID: 22496150</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Dimerization ; Female ; Glycosylation ; HEK293 Cells ; Humans ; Immunobiology ; Interleukin-15 - blood ; Interleukin-15 - chemistry ; Interleukin-15 - immunology ; Interleukin-15 Receptor alpha Subunit - blood ; Interleukin-15 Receptor alpha Subunit - immunology ; Lymphocyte Depletion - methods ; Lymphocytes - cytology ; Lymphocytes - immunology ; Melanoma - blood ; Melanoma - immunology ; Mice ; Mice, Inbred C57BL ; Skin Neoplasms - blood ; Skin Neoplasms - immunology ; Solubility</subject><ispartof>Blood, 2012-07, Vol.120 (1), p.e1-e8</ispartof><rights>2012 American Society of Hematology</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-c463t-b74428d02945c84fff2e3f606aff482bf935cf9420e0ecd7b5e6d51b9b6f64f03</citedby><cites>FETCH-LOGICAL-c463t-b74428d02945c84fff2e3f606aff482bf935cf9420e0ecd7b5e6d51b9b6f64f03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22496150$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bergamaschi, Cristina</creatorcontrib><creatorcontrib>Bear, Jenifer</creatorcontrib><creatorcontrib>Rosati, Margherita</creatorcontrib><creatorcontrib>Beach, Rachel Kelly</creatorcontrib><creatorcontrib>Alicea, Candido</creatorcontrib><creatorcontrib>Sowder, Raymond</creatorcontrib><creatorcontrib>Chertova, Elena</creatorcontrib><creatorcontrib>Rosenberg, Steven A.</creatorcontrib><creatorcontrib>Felber, Barbara K.</creatorcontrib><creatorcontrib>Pavlakis, George N.</creatorcontrib><title>Circulating IL-15 exists as heterodimeric complex with soluble IL-15Rα in human and mouse serum</title><title>Blood</title><addtitle>Blood</addtitle><description>IL-15 is an important cytokine for the function of the immune system, but the form(s) of IL-15 produced in the human body are not fully characterized. Coexpression of the single-chain IL-15 and the IL-15 receptor alpha (IL-15Rα) in the same cell allows for efficient production, surface display, and eventual cleavage and secretion of the bioactive IL-15/IL-15Rα heterodimer in vivo, whereas the single-chain IL-15 is poorly secreted and unstable. This observation led to the hypothesis that IL-15 is produced and secreted only as a heterodimer with IL-15Rα. We purified human IL-15/IL-15Rα complexes from overproducing human cell lines and developed an ELISA specifically measuring the heterodimeric form of IL-15. Analysis of sera from melanoma patients after lymphodepletion revealed the presence of circulating IL-15/IL-15Rα complexes in amounts similar to the total IL-15 quantified by a commercial IL-15 ELISA that detects both the single-chain and the heterodimeric forms of the cytokine. Therefore, in lymphodepleted cancer patients, the serum IL-15 is exclusively present in its heterodimeric form. Analysis of the form of IL-15 present in either normal or lymphodepleted mice agrees with the human data. These results have important implications for development of assays and materials for clinical applications of IL-15.</description><subject>Animals</subject><subject>Dimerization</subject><subject>Female</subject><subject>Glycosylation</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Immunobiology</subject><subject>Interleukin-15 - blood</subject><subject>Interleukin-15 - chemistry</subject><subject>Interleukin-15 - immunology</subject><subject>Interleukin-15 Receptor alpha Subunit - blood</subject><subject>Interleukin-15 Receptor alpha Subunit - immunology</subject><subject>Lymphocyte Depletion - methods</subject><subject>Lymphocytes - cytology</subject><subject>Lymphocytes - immunology</subject><subject>Melanoma - blood</subject><subject>Melanoma - immunology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Skin Neoplasms - blood</subject><subject>Skin Neoplasms - immunology</subject><subject>Solubility</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>eNp9kUtuFDEQhi1ERCaBGyDkJRtD-dGe9gYJjXhEGgkpgrVxu8sZI3d7sLtDOBYX4Uz0ZEKADauSqur_6_ER8pTDC85b8bJLOfdMAOeMA5Otklo8ICveiJYBCHhIVgCgmTJrfkrOav0CwJUUzSNyKoQymjewIp83sfg5uSmOV_Riy3hD8SbWqVJX6Q4nLLmPA5boqc_DPuEN_RanHa05zV3Co-Ty5w8aR7qbBzdSN_Z0yHNFWrHMw2NyElyq-OQunpNPb9983Lxn2w_vLjavt8wrLSfWrZUSbQ_CqMa3KoQgUAYN2oWgWtEFIxsfjBKAgL5fdw3qvuGd6XTQKoA8J6-Ovvu5G7D3OE7FJbsvcXDlu80u2n8rY9zZq3xtpTRgtFwMnt8ZlPx1xjrZIVaPKbkRl3MsB6HAGA1maVXHVl9yrQXD_RgO9gDH3sKxBziH1BHOInv294r3ot80_tyAy6OuIxZbfcTRYx8L-sn2Of5_wi8svaKC</recordid><startdate>20120705</startdate><enddate>20120705</enddate><creator>Bergamaschi, Cristina</creator><creator>Bear, Jenifer</creator><creator>Rosati, Margherita</creator><creator>Beach, Rachel Kelly</creator><creator>Alicea, Candido</creator><creator>Sowder, Raymond</creator><creator>Chertova, Elena</creator><creator>Rosenberg, Steven A.</creator><creator>Felber, Barbara K.</creator><creator>Pavlakis, George N.</creator><general>Elsevier Inc</general><general>American Society of Hematology</general><scope>6I.</scope><scope>AAFTH</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20120705</creationdate><title>Circulating IL-15 exists as heterodimeric complex with soluble IL-15Rα in human and mouse serum</title><author>Bergamaschi, Cristina ; Bear, Jenifer ; Rosati, Margherita ; Beach, Rachel Kelly ; Alicea, Candido ; Sowder, Raymond ; Chertova, Elena ; Rosenberg, Steven A. ; Felber, Barbara K. ; Pavlakis, George N.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-b74428d02945c84fff2e3f606aff482bf935cf9420e0ecd7b5e6d51b9b6f64f03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Dimerization</topic><topic>Female</topic><topic>Glycosylation</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Immunobiology</topic><topic>Interleukin-15 - blood</topic><topic>Interleukin-15 - chemistry</topic><topic>Interleukin-15 - immunology</topic><topic>Interleukin-15 Receptor alpha Subunit - blood</topic><topic>Interleukin-15 Receptor alpha Subunit - immunology</topic><topic>Lymphocyte Depletion - methods</topic><topic>Lymphocytes - cytology</topic><topic>Lymphocytes - immunology</topic><topic>Melanoma - blood</topic><topic>Melanoma - immunology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Skin Neoplasms - blood</topic><topic>Skin Neoplasms - immunology</topic><topic>Solubility</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bergamaschi, Cristina</creatorcontrib><creatorcontrib>Bear, Jenifer</creatorcontrib><creatorcontrib>Rosati, Margherita</creatorcontrib><creatorcontrib>Beach, Rachel Kelly</creatorcontrib><creatorcontrib>Alicea, Candido</creatorcontrib><creatorcontrib>Sowder, Raymond</creatorcontrib><creatorcontrib>Chertova, Elena</creatorcontrib><creatorcontrib>Rosenberg, Steven A.</creatorcontrib><creatorcontrib>Felber, Barbara K.</creatorcontrib><creatorcontrib>Pavlakis, George N.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bergamaschi, Cristina</au><au>Bear, Jenifer</au><au>Rosati, Margherita</au><au>Beach, Rachel Kelly</au><au>Alicea, Candido</au><au>Sowder, Raymond</au><au>Chertova, Elena</au><au>Rosenberg, Steven A.</au><au>Felber, Barbara K.</au><au>Pavlakis, George N.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Circulating IL-15 exists as heterodimeric complex with soluble IL-15Rα in human and mouse serum</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2012-07-05</date><risdate>2012</risdate><volume>120</volume><issue>1</issue><spage>e1</spage><epage>e8</epage><pages>e1-e8</pages><issn>0006-4971</issn><issn>1528-0020</issn><eissn>1528-0020</eissn><abstract>IL-15 is an important cytokine for the function of the immune system, but the form(s) of IL-15 produced in the human body are not fully characterized. Coexpression of the single-chain IL-15 and the IL-15 receptor alpha (IL-15Rα) in the same cell allows for efficient production, surface display, and eventual cleavage and secretion of the bioactive IL-15/IL-15Rα heterodimer in vivo, whereas the single-chain IL-15 is poorly secreted and unstable. This observation led to the hypothesis that IL-15 is produced and secreted only as a heterodimer with IL-15Rα. We purified human IL-15/IL-15Rα complexes from overproducing human cell lines and developed an ELISA specifically measuring the heterodimeric form of IL-15. Analysis of sera from melanoma patients after lymphodepletion revealed the presence of circulating IL-15/IL-15Rα complexes in amounts similar to the total IL-15 quantified by a commercial IL-15 ELISA that detects both the single-chain and the heterodimeric forms of the cytokine. Therefore, in lymphodepleted cancer patients, the serum IL-15 is exclusively present in its heterodimeric form. Analysis of the form of IL-15 present in either normal or lymphodepleted mice agrees with the human data. These results have important implications for development of assays and materials for clinical applications of IL-15.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>22496150</pmid><doi>10.1182/blood-2011-10-384362</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | Blood, 2012-07, Vol.120 (1), p.e1-e8 |
| issn | 0006-4971 1528-0020 1528-0020 |
| language | eng |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Animals Dimerization Female Glycosylation HEK293 Cells Humans Immunobiology Interleukin-15 - blood Interleukin-15 - chemistry Interleukin-15 - immunology Interleukin-15 Receptor alpha Subunit - blood Interleukin-15 Receptor alpha Subunit - immunology Lymphocyte Depletion - methods Lymphocytes - cytology Lymphocytes - immunology Melanoma - blood Melanoma - immunology Mice Mice, Inbred C57BL Skin Neoplasms - blood Skin Neoplasms - immunology Solubility |
| title | Circulating IL-15 exists as heterodimeric complex with soluble IL-15Rα in human and mouse serum |
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