CD16 is indispensable for antibody-dependent cellular cytotoxicity by human monocytes

Antibody-dependent cellular cytotoxicity (ADCC) is exerted by immune cells expressing surface Fc gamma receptors (Fc gamma Rs) against cells coated with antibody, such as virus-infected or transformed cells. CD16, the Fc gamma RIIIA, is essential for ADCC by NK cells, and is also expressed by a subset of human blood monocytes. We found that human CD16-expressing monocytes have a broad spectrum of ADCC capacities and can kill cancer cell lines, primary leukemic cells and hepatitis B virus-infected cells in the presence of specific antibodies. Engagement of CD16 on monocytes by antibody bound to target cells activated beta 2-integrins and induced TNF alpha secretion. In turn, this induced TNFR expression on the target cells, making them susceptible to TNF alpha-mediated cell death. Treatment with TLR agonists, DAMPs or cytokines, such as IFN gamma, further enhanced ADCC. Monocytes lacking CD16 did not exert ADCC but acquired this property after CD16 expression was induced by either cytokine stimulation or transient transfection. Notably, CD16+ monocytes from patients with leukemia also exerted potent ADCC. Hence, CD16+ monocytes are important effectors of ADCC, suggesting further developments of this property in the context of cellular therapies for cancer and infectious diseases.