A role for the ITAM signaling module in specifying cytokine-receptor functions

Nat Immunol. 2014 Apr;15(4):333-42. doi: 10.1038/ni.2845. Epub 2014 Mar 9.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Load
  • Cells, Cultured
  • Immunoglobulin Fc Fragments / genetics
  • Immunoglobulin Fc Fragments / metabolism
  • Immunoreceptor Tyrosine-Based Activation Motif / genetics
  • Immunoreceptor Tyrosine-Based Activation Motif / immunology*
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism*
  • Listeriosis / immunology*
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Phagocytosis / genetics
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Engineering
  • Receptor Cross-Talk / immunology*
  • Receptors, IgG / genetics
  • Receptors, IgG / metabolism
  • Receptors, Interferon / metabolism
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transcriptional Activation / drug effects

Substances

  • Immunoglobulin Fc Fragments
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, IgG
  • Receptors, Interferon
  • STAT1 Transcription Factor
  • interferon gamma receptor
  • Interferon-gamma
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Jak2 protein, mouse
  • Janus Kinase 2

Associated data

  • GEO/GSE54824