RESEARCH ARTICLE Soluble Interleukin-15 Complexes Are Generated In Vivo by Type I Interferon Dependent and Independent Pathways

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 sig-nals leading to the generation of sIL-15 complexes. In this study, we show that sIL-15 com-plexes 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 metalloprotei-nase 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 demonstrat-ing 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 in-duction of sIL-15 complexes by Poly I:C stimulation or total body irradiation (TBI) was im-paired in IFNAR-/- mice. Interestingly, serum sIL-15 complexes were also induced in mic