Toxoplasma gondii down-regulates MHC class II gene expression and antigen presentation by murine macrophages via...

The obligate intracellular protozoan parasite Toxoplasma gondii is able to establish persistent infections within human and animal hosts. We have shown recently that T. gondii down-regulates IFN-gamma-induced MHC class II expression in murine bone marrow-derived macrophages (BMM4). As shown in this study, the capacity of IFN-gamma-activated murine BMMphi to present ovalbumin to CD4+ T cell hybridomas was dose-dependently inhibited by T. gondii. IFN-gamma-induced up-regulation of H2-Aa, H2-Ab, H2-Eb, H2-Ma, H2-Mb, H2-Oa and invariant chain transcripts was prominently down-regulated by T. gondii. Furthermore, mRNA levels of class II transactivator and interferon-regulatory factor-1 were significantly diminished. Electromobility shift assays demonstrated a decrease in the binding activity of nuclear extracts to the IFN-gamma-activated site after infection with T. gondii, indicating parasitic interference with IFN-gamma-induced signaling. However, neither the expression of the IFN-gammaR nor the IFN-gamma-induced tyrosine phosphorylation of IFN-gammaR alpha chain and signal transducer and activator of transcription (STAT) 1alpha was diminished by T. gondii. IFN-gamma-induced nuclear translocation of STAT1alpha was nevertheless inhibited after infection as demonstrated by immunofluorescence microscopy and subcellular fractionation analyses. In conclusion, this novel mechanism of microbial interference with MHC class II gene expression may contribute to intracellular survival and establishment of persistent infection with T. gondii.