The effect of silencing NKG2D through RNA interference on receptor functions in interleukin-2-activated human natural killer cells.

Natural killer (NK) cells are effectors of the innate immunity involved in tumor surveillance. NKG2D is a potent activating receptor eliciting cytokine and cytolytic NK responses upon recognition of tumor-associated ligands. We engineered primary interleukin (IL)-2-activated human NK cells to express constitutively low levels of NKG2D by lentiviral delivery of small interfering RNA. NKG2D-mediated effector functions were strongly impaired in NKG2D(low) NK cells. Reduction of NKG2D surface expression to 15%, corresponding to receptor levels in resting NK cells, rendered cells fully insensitive to NKG2D triggering. These data underscore the importance of NKG2D receptor cell surface density and suggest a threshold of expression for optimal reactivity of human NK cells.