Immune complexes suppress IFN-γ signaling by activation of the Fc-γRI pathway

Antigen-driven immune responses are modulated by immune complexes (ICs), in part through their ability to inhibit IFN-gamma-dependent MHC Class 11 expression. We have demonstrated previously that ICs dramatically inhibit IFN-gamma-induced activation of human monocytes through the suppression of the JAK/STAT signaling pathway. In the current study, we further explore the mechanisms by which ICs regulate IFN-gamma activation of human monocytes. Consistent with previous studies in monocytes pretreated with ICs, there was a reduction in steady-state levels of RNA by real-time RT-PCR of the IFN-inducible protein 10 gene as well as the Fc gamma RI gene. Pull-down assays confirm that IC pretreatment inhibits IFN-gamma-induced STAT1 phosphorylation without affecting the ability of STAT1 to bind to the STAT1-binding domain of the IFN-gamma receptor. In addition, the inhibitory function of ICs was reduced when cells from the FcR common gamma-chain knockout mice were used, supporting the role of the Fc gamma RI in this inhibitory pathway. It is unexpected that ICs also require the phosphatase Src homology-2-containing tyrosine phosphatase 1 (SHP-1) to inhibit IFN-gamma induction, as demonstrated by studies with cells from the SHP-1 knockout (motheaten) mice. These data suggest a mechanism of IC-mediated inhibition of IFN-gamma signaling, which requires the ITAM-containing Fc gamma RI, as well as the ITIM-dependent phosphatase SHP-1, ultimately resulting in the suppression of STAT1 phosphorylation.