Antibody Fc receptor CD16a mediates natural killer cell activation via mechanotransduction of piconewton forces.

Natural killer (NK) cells eliminate target cells through antibody-dependent cell-mediated cytotoxicity (ADCC), initiated by CD16a (FcγRIIIa) recognizing the Fc region of antibodies bound to the target cell surface. While the recognition is considered to be driven by CD16a-Fc binding avidity, it fails to explain why Fc multimers inhibit ADCC in solution rather than trigger it. Here, we reveal that CD16a transduces piconewton forces and acts as a mechanosensor to facilitate NK activation. We demonstrate that CD16a force and the actin foci formation associated with it are essential for the phosphorylation of mechanosensitive adaptor Cas-L and signaling adaptor LAT (linker of activation of T cells), reshaping NK cell cytoskeletal dynamics and signaling. Our findings show that NK activation is an intricate process that integrates both biochemical and biophysical information and provide fresh mechanistic insight for immunoengineering.