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. ADCC is initiated by the engagement of an Fc gamma receptor CD16 with an Fc portion of the antibody, leading to phosphorylation of the CD3 zeta chain (CD3 zeta) and Fc receptor gamma chain (FcR gamma) as well as downstream signaling activation. Though CD3 zeta and FcR gamma were thought to have overlapping roles in NK cell ADCC, several groups have reported that CD3 zeta-mediated signals trigger a more robust ADCC. However, few studies have illustrated the direct contribution of CD3 zeta in HIV-1-specific ADCC. To further understand the roles played by CD3 zeta in HIV-1-specific ADCC, we developed a CD3 zeta knockdown system in primary human NK cells. We observed that HIV-1-specific ADCC was inhibited by CD3 zeta perturbation. In summary, we demonstrated that CD3 zeta 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.