Paired activating and inhibitory Fc receptors set a time limit for phagocytosis. IgG antibodies bind to target molecules on infected cells or pathogens. IgG is recognized by Fc receptors in macrophages and triggers phagocytosis. The Fc receptor family consists of several activating receptors and one inhibitory receptor, Fc receptor IIB (FcRIIB), which all respond to IgG. Why has evolution selected for an inhibitory receptor that responds to the same molecule as the activating receptor? Why can macrophages not more simply adjust their appetite by controlling the activating receptor alone? Progress on FcRIIB signaling has been limited to B cells, where FcRIIB is the only Fc receptor expressed. These studies show that FcRIIB recruits an inositol phosphatase SHIP-1, which depletes the key signaling lipid PIP3. In most immune cells, FcRIIB is expressed alongside the activating Fc receptors making it more difficult to selectively assay. To study how FcRIIB regulates phagocytosis, we designed a synthetic receptor that utilizes complimentary DNA strands to selectively activate FcRIIB independently from the activating receptors in this family. We examined how FcRIIB activation impacts the kinetics of phagocytosis, and found that FcRIIB caused phagocytosis to fail in the final stage before target internalization. We then developed an in silico model describing how the activating and inhibitory Fc receptors impact PIP3. Our model suggests that engaging both the activating and inhibitory Fc receptors generates an incoherent feed forward loop, where PIP3 is rapidly generated by the activating arm and slowly depleted by the inhibitory arm. This type of regulation may benefit a macrophage by limiting phagocytic activity of targets that are too large or otherwise difficult to engulf, retaining phagocytic capacity for other targets.
Meghan A. Morrissey (Sun,) studied this question.