Immune complexes suppress IFN‐γ signaling by activation of the FcγRI pathway

Antigen‐driven immune responses are modulated by immune complexes (ICs), in part through their ability to inhibit IFN‐γ‐dependent MHC Class II expression. We have demonstrated previously that ICs dramatically inhibit IFN‐γ‐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‐γ 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 FcγRI gene. Pull‐down assays confirm that IC pretreatment inhibits IFN‐γ‐induced STAT1 phosphorylation without affecting the ability of STAT1 to bind to the STAT1‐binding domain of the IFN‐γ receptor. In addition, the inhibitory function of ICs was reduced when cells from the FcR common γ‐chain knockout mice were used, supporting the role of the FcγRI 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‐γ 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‐γ signaling, which requires the ITAM‐containing FcγRI, as well as the ITIM‐dependent phosphatase SHP‐1, ultimately resulting in the suppression of STAT1 phosphorylation.