Editors' ChoiceImmunology

Context-Dependent Antimicrobial Responses

Science Signaling  25 Mar 2014:
Vol. 7, Issue 318, pp. ec80
DOI: 10.1126/scisignal.2005299

During microbial infections, immune cells such as T cells and natural killer cells produce the cytokine interferon-γ (IFN-γ), whereas plasma cells produce antibodies in the form of immunoglobulin G (IgG). Macrophages have both IFN-γ receptors (IFN-γR) and FcγRI receptors, which bind to monomeric IgG. Whereas IFN-γR signals through a Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway to drive target gene expression, FcγR1 signals through immunoreceptor tyrosine-based activation motifs (ITAMs) in associated homodimeric FcRγ proteins. Bezbradica et al. found that IFN-γR colocalized with FcγR1 during FcγR1-mediated phagocytosis of IgG-coated beads by mouse bone marrow–derived macrophages. Coimmunoprecipitation experiments showed that the IFN-γR–associated Jak2 protein formed a complex with FcRγ, although canonical signaling by either IFN-γR or FcγRI was not dependent on the presence of the other receptor. However, gene expression analysis showed that expression of a subset of IFN-γ target genes, including the gene encoding inducible nitric oxide synthase (Nos2) and other components of the antimicrobial response, was reduced in FcγR-deficient macrophages compared with that in wild-type macrophages. When stimulated with IFN-γ, IgG-deficient mice expressed Nos2 poorly, which suggested that signaling through FcγRI was required. Inhibition of phosphoinositide 3-kinase blocked signaling through FcγRI and inhibited the IFN-γ–dependent expression of Nos2. Compared with wild-type mice, FcγR-deficient mice were more susceptible to infection with Listeria monocytogenes, whose early replication is inhibited by IFN-γ. Together, these data suggest that a subset of genes involved in the antimicrobial response requires both JAK-STAT and ITAM-dependent signaling for their expression. As Daëron and Vivier discuss in commentary, these results suggest that macrophages use both IFN-γR and FcγRI as coincidence detectors to sense microbial context, which begs the question of what other combinations of receptors might be used by these and other immune cell types.

J. S. Bezbradica, R. K. Rosenstein, R. A. DeMarco, I. Brodsky, R. Medzhitov, A role for the ITAM signaling module in specifying cytokine-receptor functions. Nat. Immunol. 15, 333–342 (2014). [PubMed]

M. Daëron, E. Vivier, Coincidence detection of antibodies and interferon for sensing microbial context. Nat. Immunol. 15, 316–317 (2014). [PubMed]