title: Soluble interleukin-15 complexes are generated in vivo by type I interferon dependent and independent pathways.
abstract: Interleukin (IL)-15 associates with IL-15Rα on the cell surface where it can be cleaved into soluble cytokine/receptor complexes that have the potential to stimulate CD8 T cells and NK cells. Unfortunately, little is known about the in vivo production of soluble IL-15Rα/IL-15 complexes (sIL-15 complexes), particularly regarding the circumstances that induce them and the mechanisms responsible. The main objective of this study was to elucidate the signals leading to the generation of sIL-15 complexes. In this study, we show that sIL-15 complexes are increased in the serum of mice in response to Interferon (IFN)-α. In bone marrow derived dendritic cells (BMDC), IFN-α increased the activity of ADAM17, a metalloproteinase implicated in cleaving IL-15 complexes from the cell surface. Moreover, knocking out ADAM17 in BMDCs prevented the ability of IFN-α to induce sIL-15 complexes demonstrating ADAM17 as a critical protease mediating cleavage of IL-15 complexes in response to type I IFNs. Type I IFN signaling was required for generating sIL-15 complexes as in vivo induction of sIL-15 complexes by Poly I:C stimulation or total body irradiation (TBI) was impaired in IFNAR-/- mice. Interestingly, serum sIL-15 complexes were also induced in mice infected with Vesicular stomatitis virus (VSV) or mice treated with agonistic CD40 antibodies; however, sIL-15 complexes were still induced in IFNAR-/- mice after VSV infection or CD40 stimulation indicating pathways other than type I IFNs induce sIL-15 complexes. Overall, this study has shown that type I IFNs, VSV infection, and CD40 stimulation induce sIL-15 complexes suggesting the generation of sIL-15 complexes is a common event associated with immune activation. These findings reveal an unrealized mechanism for enhanced immune responses occurring during infection, vaccination, inflammation, and autoimmunity.
authors.affiliation: Departments of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Immunology Graduate Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, United States of America.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Anthony
authors.affiliation: Departments of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Howard
authors.affiliation: Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Yared
authors.initials: Y
authors.lastname: Hailemichael
authors.affiliation: Immunology Graduate Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, United States of America; Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Willem W
authors.initials: WW
authors.lastname: Overwijk
authors.affiliation: Departments of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Immunology Graduate Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, United States of America.
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Schluns
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism; D016898:Interferon-alpha / Q000502:physiology*; D019409:Interleukin-15 / Q000097:blood*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D054243:Vesicular Stomatitis / Q000097:blood; D014916:Whole-Body Irradiation
chemical_list: D019013:CD40 Antigens; D016898:Interferon-alpha; D019409:Interleukin-15; D053633:Receptor, Interferon alpha-beta