CD56 dim CD16 dim NK cells are the dominant effector cells against HIV-infected primary T-cells
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Despite being rare among circulating natural killer (NK) cells and expressing 10-fold less CD16 than the predominant CD56 dim CD16 bright population, CD56 dim CD16 dim 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 CD56 dim CD16 bright 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 CD56 dim CD16 dim 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 (CD56 dim CD16 negative cells dominate against K562 cells), and identify high-NKG2D CD56 dim CD16 dim cells as the effector population HIV therapies should reproduce.
Impact Statement
A rare natural killer cell subset that makes up only a few percent of circulating NK cells, yet is enriched in the people who control HIV for years without medication, turns out to be the dominant killer of HIV-infected cells, far outperforming the common subset long assumed to do the job, and this work shows how these cells recognize and repeatedly attack infected targets, pointing to the specific effector that future cell-based therapies might use to help people with HIV stay healthy without lifelong drugs.
