1. Size-Dependent Segregation Controls Macrophage Phagocytosis of Antibody-Opsonized Targets.
- Author
-
Bakalar MH, Joffe AM, Schmid EM, Son S, Podolski M, and Fletcher DA
- Subjects
- Animals, Antibodies, Monoclonal chemistry, Antigens genetics, Antigens immunology, Carcinoembryonic Antigen chemistry, Carcinoembryonic Antigen genetics, Carcinoembryonic Antigen immunology, Gene Editing, Integrins metabolism, Leukocyte Common Antigens chemistry, Leukocyte Common Antigens genetics, Leukocyte Common Antigens immunology, Macrophages cytology, Mice, Opsonin Proteins chemistry, Phosphorylation, RAW 264.7 Cells, Receptors, Fc immunology, Receptors, Fc metabolism, Unilamellar Liposomes chemistry, Antibodies, Monoclonal immunology, Antigens chemistry, Macrophages immunology, Opsonin Proteins metabolism, Phagocytosis
- Abstract
Macrophages protect the body from damage and disease by targeting antibody-opsonized cells for phagocytosis. Though antibodies can be raised against antigens with diverse structures, shapes, and sizes, it is unclear why some are more effective at triggering immune responses than others. Here, we define an antigen height threshold that regulates phagocytosis of both engineered and cancer-specific antigens by macrophages. Using a reconstituted model of antibody-opsonized target cells, we find that phagocytosis is dramatically impaired for antigens that position antibodies >10 nm from the target surface. Decreasing antigen height drives segregation of antibody-bound Fc receptors from the inhibitory phosphatase CD45 in an integrin-independent manner, triggering Fc receptor phosphorylation and promoting phagocytosis. Our work shows that close contact between macrophage and target is a requirement for efficient phagocytosis, suggesting that therapeutic antibodies should target short antigens in order to trigger Fc receptor activation through size-dependent physical segregation., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF