Gelatinase B/matrix metalloproteinase-9 and other neutrophil proteases switch off interleukin-2 activity

Interleukin 2 (IL-2) is critical for T cell development and homeostasis, being a key regulator of adaptive immune responses in autoimmunity, hypersensitivity reactions and cancer. Therefore, its abundance in serum and peripheral tissues needs tight control. Here, we described a new mechanism contrib...

Full description

Saved in:
Bibliographic Details
Published inBiochemical journal Vol. 476; no. 15; p. 2191
Main Authors Rybakin, Vasily, Stas, Melissa, Ugarte-Berzal, Estefania, Noppen, Sam, Vandooren, Jennifer, Van Aelst, Ilse, Liekens, Sandra, Proost, Paul, Opdenakker, Ghislain
Format Journal Article
LanguageEnglish
Published England 09.08.2019
Subjects
Animals
Cell Line
Humans
Interleukin-2 - genetics
Interleukin-2 - metabolism
Matrix Metalloproteinase 9 - genetics
Matrix Metalloproteinase 9 - metabolism
Mice
Neutrophils - enzymology
Signal Transduction
T-Lymphocytes, Regulatory - immunology
metalloproteases
cell proliferation
interleukin 2
neutrophils
IL-2 receptor
Online AccessGet more information

Cover

More Information
Summary:Interleukin 2 (IL-2) is critical for T cell development and homeostasis, being a key regulator of adaptive immune responses in autoimmunity, hypersensitivity reactions and cancer. Therefore, its abundance in serum and peripheral tissues needs tight control. Here, we described a new mechanism contributing to the immunobiology of IL-2. We demonstrated, both in biochemical and cell-based assays, that IL-2 is subject to proteolytic processing by neutrophil matrix metalloproteinase-9 (MMP-9). IL-2 fragments produced after cleavage by MMP-9 remained linked by a disulfide bond and displayed a reduced affinity for all IL-2 receptor subunits and a distinct pattern and timing of signal transduction. Stimulation of IL-2-dependent cells, including murine CTLL-2 and primary human regulatory T cells, with cleaved IL-2 resulted in significantly decreased proliferation. The concerted action of neutrophil proteases destroyed IL-2. Our data suggest that in neutrophil-rich inflammatory conditions , neutrophil MMP-9 may reduce the abundance of signaling-competent IL-2 and generate a fragment that competes with IL-2 for receptor binding, whereas the combined activity of granulocyte proteases has the potential to degrade and thus eliminate bioavailable IL-2.
ISSN:1470-8728
DOI:10.1042/BCJ20180382