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

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-gamma (IFN-gamma R) and the ITAM adaptor Fc gamma as an example, we found that IFN-gamma modified responses of the phagocytic antibody receptor Fc gamma RI (CD64) to specify cell-autonomous antimicrobial functions. Unexpectedly, we also found that in peritoneal macrophages, IFN-gamma R itself required tonic signaling from Fc gamma through the kinase PI(3) K for the induction of a subset of IFN-gamma-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.