title: Circulating IL-15 exists as heterodimeric complex with soluble IL-15Rα in human and mouse serum.
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.
authors.affiliation: Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. bergamac@mail.nih.gov
authors.forename: Cristina
authors.initials: C
authors.lastname: Bergamaschi
authors.forename: Jenifer
authors.initials: J
authors.lastname: Bear
authors.forename: Margherita
authors.initials: M
authors.lastname: Rosati
authors.forename: Rachel Kelly
authors.initials: RK
authors.lastname: Beach
authors.forename: Candido
authors.initials: C
authors.lastname: Alicea
authors.forename: Raymond
authors.initials: R
authors.lastname: Sowder
authors.forename: Elena
authors.initials: E
authors.lastname: Chertova
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Felber
authors.forename: George N
authors.initials: GN
authors.lastname: Pavlakis
mesh_terms: D000818:Animals; D019281:Dimerization; D005260:Female; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D019409:Interleukin-15 / Q000097:blood* / Q000737:chemistry* / Q000276:immunology; D053720:Interleukin-15 Receptor alpha Subunit / Q000097:blood* / Q000276:immunology*; D008212:Lymphocyte Depletion / Q000379:methods; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D008545:Melanoma / Q000097:blood / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D012878:Skin Neoplasms / Q000097:blood / Q000276:immunology; D012995:Solubility
chemical_list: D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit