CD56dimCD16dim NK cells are the dominant effector cells against HIV-infected primary T-cells

Despite being rare among circulating natural killer (NK) cells and expressing 10-fold less CD16 than the predominant CD56dimCD16bright population, CD56dimCD16dim NK cells are expanded in HIV long-term elite controllers, yet their capacity to kill HIV-infected cells remained untested. Here, we show that these rare cells are the dominant effectors against HIV-infected T-cells, mediating approximately 4-fold higher direct cytotoxicity and 3-4-fold higher antibody-dependent cellular cytotoxicity (ADCC) than CD56dimCD16bright cells, and serially engaging multiple targets. This advantage is intrinsic, unexplained by cytotoxic granule content or inhibitory receptors recognizing MHC class I. Direct killing depends on NKG2D recognition of Vpr-induced ligands, with NKG2D elevated on CD56dimCD16dim cells; ADCC requires both NKG2D and ADAM17-mediated CD16 turnover for serial engagement. These findings explain the elite-controller reorganization, reveal that NK effector dominance is target-tuned rather than fixed (CD56dimCD16negative cells dominate against K562 cells), and identify high-NKG2D CD56dimCD16dim cells as the effector population HIV therapies should reproduce.