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, CD56neg population of NK cells that differed transcriptionally, epigenetically, and phenotypically from CD56dim NK cells, including decreased expression of PLZF and the Fc receptor gamma-chain, increased histone methylation, and increased protein expression of LAG-3, KIR, and LILRB1. CD56neg NK cells were highly functional and displayed greater antibody-dependent cellular cytotoxicity than CD56dim NK cells. Higher frequencies of CD56neg NK 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 falciparum is required to maintain this modified, adaptive-like NK cell subset.

Automated summary

Repeated malaria exposure leads to expansion of atypical CD56neg NK cells in Ugandan children, characterized by transcriptional, epigenetic, and phenotypic differences from CD56dim NK cells. CD56neg NK cells display enhanced functionality and greater antibody-dependent cellular cytotoxicity. Higher frequencies of CD56neg NK cells are associated with protection against symptomatic malaria. Continuous exposure to Plasmodium falciparum is necessary to maintain this modified, adaptive-like NK cell subset, as frequencies rapidly decline after reductions in malaria transmission.