Abnormal IFN-gamma-dependent immunoproteasome modulation by Trypanosoma cruzi-infected macrophages

Proteasomes are the main producers of Ag loaded onto MHC class I molecules. Following IFN-gamma 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 T(helper)1 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 (MuPhi) 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 MuPhi reduces IFN-gamma-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 MuPhi, 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-gamma-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.