Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA; UC Berkeley/UC San Francisco Graduate Group in Bioengineering, Berkeley, CA 94720, USA.
Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA.
Cell. 2018 Jun 28;174(1):131-142.e13. doi: 10.1016/j.cell.2018.05.059.
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.
巨噬细胞通过靶向抗体包被的细胞进行吞噬作用来保护身体免受损伤和疾病的侵害。尽管可以针对具有不同结构、形状和大小的抗原产生抗体，但不清楚为什么有些抗原比其他抗原更能有效引发免疫反应。在这里，我们定义了一个抗原高度阈值，该阈值调节巨噬细胞对工程抗原和癌症特异性抗原的吞噬作用。使用抗体包被的靶细胞重建模型，我们发现对于将抗体定位在距靶表面 >10nm 处的抗原，吞噬作用会显著受损。降低抗原高度以整合素独立的方式驱动抗体结合的 Fc 受体与抑制性磷酸酶 CD45 的分离，触发 Fc 受体磷酸化并促进吞噬作用。我们的工作表明，巨噬细胞和靶细胞之间的紧密接触是有效吞噬作用的要求，这表明治疗性抗体应该针对短抗原，以便通过大小依赖性物理分离来触发 Fc 受体的激活。
