LAUSR

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 γ-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. Description Repeated malaria in children is followed by expansion of functional CD56neg NK cells associated with protection from symptomatic malaria. Protection amidst continuous exposure Natural killer (NK) cells have been linked to protective immune responses to Plasmodium falciparum, a parasite that causes malaria. Ty et al. identified an atypical CD56neg NK cell subset that expands during repeated parasite exposure and correlated with protection against symptomatic malaria. They profiled NK cells in a cohort of 264 Ugandan children using transcriptional, epigenetic, and phenotypic analysis. CD56neg NK cells were distinct from CD56dim NK cells, with decreased expression of PLZF and Fc receptor γchain and greater KIR, LAG-3, and LILRB1 protein expression. CD56neg NK cells displayed antibody dependent cellular cytotoxicity, and higher CD56neg NK cell frequencies correlated with protection against symptomatic malaria. In the absence of malaria transmission, CD56neg NK cells rapidly decreased. These findings a suggest that continuous exposure to P. falciparum is needed to maintain this NK cell subset. —CF