Malaria-driven expansion of adaptive-like functional CD56-negative NK cells correlates with clinical immunity to malaria

Natural killer (NK) cells likely play an important role in immunity to malaria, but the effect of repeated malaria on NK cell responses remains unclear. Here, we comprehensively profiled the NK cell response in a cohort of 264 Ugandan children. Repeated malaria exposure was associated with expansion of an atypical, CD56negpopulation of NK cells that differed transcriptionally, epigenetically, and phenotypically from CD56dimNK cells, including decreased expression of PLZF and the Fc receptor γ-chain, increased histone methylation, and increased protein expression of LAG-3, KIR, and LILRB1. CD56negNK cells were highly functional and displayed greater antibody-dependent cellular cytotoxicity than CD56dimNK cells. Higher frequencies of CD56negNK cells were associated with protection against symptomatic malaria and high parasite densities. After marked reductions in malaria transmission, frequencies of these cells rapidly declined, suggesting that continuous exposure to Plasmodium falciparumis required to maintain this modified, adaptive-like NK cell subset.