Knockdowns of CD3zeta chain in Primary NK Cells Illustrate Modulation of Antibody-Dependent Cellular Cytotoxicity against Human Immunodeficiency Virus-1.

Multifaceted natural killer (NK) cell activities are indispensable for controlling human immunodeficiency virus (HIV)-1 transmission and pathogenesis. Among the diverse functions of NK cells, antibody-dependent cellular cytotoxicity (ADCC) has been shown to predict better HIV-1 protection (1-3). ADCC is initiated by the engagement of an Fcg receptor CD16 with an Fc portion of the antibody, leading to phosphorylation of the CD3z chain (CD3) and Fc receptor g chain (FcRg) as well as downstream signaling activation. Though CD3 and FcR were thought to have overlapping roles in NK cell ADCC, several groups have reported that CD3-mediated signals trigger a more robust ADCC (4-8). However, few studies have illustrated the direct contribution of CD3z in HIV-1-specific ADCC. To further understand the roles played by CD3 in HIV-1-specific ADCC, we developed a CD3z knockdown system in primary human NK cells. We observed that HIV-1-specific ADCC was inhibited by CD3z perturbation. In summary, we demonstrated that CD3 is important for eliciting HIV-1-specific ADCC, and this dynamic can be utilized for NK cell immunotherapeutics against HIV-1 infection and other diseases.