Soluble interleukin-15 complexes are generated in vivo by type I interferon dependent and independent pathways

Scott M Anthony; Megan E Howard; Yared Hailemichael; Willem W Overwijk; Kimberly S Schluns

doi:10.1371/journal.pone.0120274

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Soluble interleukin-15 complexes are generated in vivo by type I interferon dependent and independent pathways

Journal article

Open access

Peer reviewed

Soluble interleukin-15 complexes are generated in vivo by type I interferon dependent and independent pathways

Scott M Anthony, Megan E Howard, Yared Hailemichael, Willem W Overwijk and Kimberly S Schluns

PloS one, Vol.10(3), pp.e0120274-e0120274

2015

DOI: 10.1371/journal.pone.0120274

PMCID: PMC4354909

PMID: 25756182

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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.

Animals

CD40 Antigens - metabolism

Cells, Cultured

Dendritic Cells - metabolism

Interferon-alpha - physiology

Interleukin-15 - blood

Mice, Inbred C57BL

Mice, Knockout

Receptor, Interferon alpha-beta - metabolism

Vesicular Stomatitis - blood

Whole-Body Irradiation

Details

Title: Subtitle: Soluble interleukin-15 complexes are generated in vivo by type I interferon dependent and independent pathways
Creators: Scott M Anthony - The University of Texas MD Anderson Cancer Center
Megan E Howard - The University of Texas MD Anderson Cancer Center
Yared Hailemichael - The University of Texas MD Anderson Cancer Center
Willem W Overwijk - The University of Texas MD Anderson Cancer Center
Kimberly S Schluns - The University of Texas MD Anderson Cancer Center
Resource Type: Journal article
Publication Details: PloS one, Vol.10(3), pp.e0120274-e0120274
DOI: 10.1371/journal.pone.0120274
PMID: 25756182
PMCID: PMC4354909
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science
Grant note: R01 CA143077 / NCI NIH HHS T32 CA009598 / NCI NIH HHS CA009598 / NCI NIH HHS
Language: English
Date published: 2015
Academic Unit: Pathology
Record Identifier: 9984185180702771

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