IFN-α induces soluble IL-15 complexes via ADAM17 mediated cleavage (CCR3P.206)

Type I Interferons (IFN) are potent inducers of IL-15 transcription and cell surface expression. Previous studies have shown that sIL-15 complexes, which act as IL-15 agonists, are generated by TLR stimulation and after non-myeloablative lymphodepletion. Since TLR stimulation induces type I IFNs, we investigated the role of type I IFNs in generating sIL-15 complexes. We report that treatment with a plasmid inducing IFN-α production potently increased serum sIL-15 complexes levels in mice. Production of sIL-15 complexes by bone marrow derived dendritic cells (BMDC) also increased after treatment with IFN-α in an IFNAR-dependent manner. Increases in sIL-15 complexes after total body irradiation coincided with appearance of serum IFN-α and were significantly impaired in the absence of Type I IFN signaling. In addition, we found that IFN-α induced activity of the metalloprotease, ADAM17 in BMDCs, which was critical as induction of sIL-15 complexes by IFN-α was abolished after deleting ADAM17. We also determined whether sIL-15 complexes are generated during a Vesicular stomatitis virus (VSV) infection as VSV induces Type I IFNs. One day after infection, sIL-15 complexes are transiently induced, which was surprisingly unabated in the absence of Type I IFN signaling. Overall, our findings show that Type I IFNs induce production of sIL-15 complexes by activating ADAM17-mediated cleavage, thus identifying a new mechanism regulating sIL-15 complexes during inflammation.