Diverse cellular responses to external cues are controlled by a small number of signal-transduction pathways, but how the specificity of functional outcomes is achieved remains unclear. Here we describe a mechanism for signal integration based on the functional coupling of two distinct signaling pathways widely used in leukocytes: the ITAM pathway and the Jak-STAT pathway. Through the use of the receptor for interferon-γ (IFN-γR) and the ITAM adaptor Fcγ as an example, we found that IFN-γ modified responses of the phagocytic antibody receptor FcγRI (CD64) to specify cell-autonomous antimicrobial functions. Unexpectedly, we also found that in peritoneal macrophages, IFN-γR itself required tonic signaling from Fcγ through the kinase PI(3)K for the induction of a subset of IFN-γ-specific antimicrobial functions. Our findings may be generalizable to other ITAM and Jak-STAT signaling pathways and may help explain signal integration by those pathways.
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Animals, Bacterial Load, Cells, Cultured, Immunoglobulin Fc Fragments, Immunoreceptor Tyrosine-Based Activation Motif, Interferon-gamma, Janus Kinase 2, Listeriosis, Macrophages, Mice, Mice, Inbred Strains, Mice, Knockout, Nitric Oxide Synthase Type II, Phagocytosis, Phosphoinositide-3 Kinase Inhibitors, Protein Engineering, Receptor Cross-Talk, Receptors, IgG, Receptors, Interferon, STAT1 Transcription Factor, Signal Transduction, Transcriptional Activation