Overcoming steric inhibition of antibody-dependent phagocytosis with tall adhesions

Macrophages contribute to our immune defenses by phagocytosing pathogens and diseased cells. To accomplish this, they must first establish close contacts between receptors on their membranes and antibodies or other ligands decorating target cells. However, macrophage binding to the target can be disrupted by the presence of tall neighboring proteins and glycans-'bystander' molecules-that sterically prevent the two surfaces from coming into close contact. Counterintuitively, this inhibition can be overcome by the addition of even taller binding proteins between the macrophage and target cell, albeit at low concentrations. Using live cell and in vitro experiments, theory, and computer simulations, we show that tall binders can promote close contact that enables phagocytosis, even in the presence of bystander proteins that would normally block close contact.