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bioRxiv · 10.64898/2026.09.21.753242

Inhibitory Fc Receptor sets a time limit on macrophage response to IgG

Bond, A.·Snyder, E. T.·Manion, A.·Hardy, C.·Kieu, K.·Wilson, M. Z.·Yeung, E. A.·Morrissey, M. A.
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Abstract

Antibodies engage both activating Fc Receptors and the inhibitory receptor Fc{gamma}RIIB. Why macrophages need a dedicated inhibitory receptor rather than simply tuning activating receptor signaling is unclear. Using DNA-based chimeric receptors and in silico modeling, we independently controlled activating and inhibitory Fc Receptors. We found that Fc{gamma}RIIB imposed a time limit on macrophage phagocytosis and ERK signaling. The time limit is due to activating Fc Receptors converting PI(4,5)P2 to PI(3,4,5)P3, which is subsequently converted to PI(3,4)P2 by Fc{gamma}RIIB. This leads to a pulse of active signaling, which is sufficient for phagocytosis of small bacteria-sized targets but not phagocytosis of large targets and TNF secretion. Unlike engaging Fc{gamma}RIIB, reducing activating Fc Receptor signaling decreased initiation of phagocytosis, the speed of PI(3,4,5)P3 generation, and the amplitude of ERK signaling. Our results demonstrate that Fc{gamma}RIIB controls the duration of IgG signaling, while the activating Fc Receptors control sensitivity.

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Bond, A., Snyder, E. T., Manion, A., Hardy, C., Kieu, K., Wilson, M. Z., Yeung, E. A., Morrissey, M. A.. 2026-09-27. Inhibitory Fc Receptor sets a time limit on macrophage response to IgG. https://doi.org/10.64898/2026.09.21.753242

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