Abnormal IFN‐γ‐dependent immunoproteasome modulation by Trypanosoma cruzi‐infected macrophages
M Bergeron, J Blanchette, P Rouleau… - Parasite …, 2008 - Wiley Online Library
M Bergeron, J Blanchette, P Rouleau, M Olivier
Parasite immunology, 2008•Wiley Online LibraryProteasomes are the main producers of Ag loaded onto MHC class I molecules. Following
IFN‐γ stimulation however, the constitutive subunits of the proteasome are replaced by the
immunosubunits low molecular weight protein 2 (LMP2), multicatalytic endopeptidase
complex‐like 1 and low molecular weight protein 7 (LMP7), which generally heighten the
immunogenecity of proteasome generated epitopes. Given that Trypanosoma cruzi, the
aetiological agent of Chagas' disease, elicits a Thelper1 response from its host if the …
IFN‐γ stimulation however, the constitutive subunits of the proteasome are replaced by the
immunosubunits low molecular weight protein 2 (LMP2), multicatalytic endopeptidase
complex‐like 1 and low molecular weight protein 7 (LMP7), which generally heighten the
immunogenecity of proteasome generated epitopes. Given that Trypanosoma cruzi, the
aetiological agent of Chagas' disease, elicits a Thelper1 response from its host if the …
Summary
Proteasomes are the main producers of Ag loaded onto MHC class I molecules. Following IFN‐γ stimulation however, the constitutive subunits of the proteasome are replaced by the immunosubunits low molecular weight protein 2 (LMP2), multicatalytic endopeptidase complex‐like 1 and low molecular weight protein 7 (LMP7), which generally heighten the immunogenecity of proteasome generated epitopes. Given that Trypanosoma cruzi, the aetiological agent of Chagas’ disease, elicits a Thelper1 response from its host if the infection is to be contained, the aim of this study was to verify whether this parasite modulates J774 and B10R mouse macrophage (ΜΦ) immunoproteasome subunit and MHC class I expressions and, if so, identify the mechanism(s) responsible for that modulation. Results show that T. cruzi infection of mouse ΜΦ reduces IFN‐γ‐mediated immunoproteasome synthesis, along with MHC class I mRNA synthesis and cell surface expression. The infection by T. cruzi induces the release of reactive oxygen species (ROS) from ΜΦ, and those ROS significantly inhibit protein tyrosine phosphatase activity, thereby leading to the activation of the SAPK/JNK signalling pathway, which is responsible for the observed IFN‐γ‐mediated immunoproteasome synthesis and MHC class I down‐regulation. To our knowledge, this is the first report that specifically identifies a mechanism by which a pathogen achieves immunoproteasome down‐modulation.
Wiley Online Library