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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.

Original publication




Journal article


Nature immunology

Publication Date





333 - 342


Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.


Cells, Cultured, Macrophages, Animals, Mice, Inbred Strains, Mice, Knockout, Mice, Receptors, Interferon, Receptors, IgG, Protein Engineering, Signal Transduction, Phagocytosis, Receptor Cross-Talk, Immunoglobulin Fc Fragments, STAT1 Transcription Factor, Nitric Oxide Synthase Type II, Janus Kinase 2, Interferon-gamma, Transcriptional Activation, Listeriosis, Phosphatidylinositol 3-Kinases, Bacterial Load, Immunoreceptor Tyrosine-Based Activation Motif