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SUMMARY Cerebral malaria is a deadly complication of Plasmodium infection and involves blood brain barrier (BBB) disruption following infiltration of white blood cells. During experimental cerebral malaria (ECM), mice inoculated with Plasmodium berghei ANKA‐infected red blood cells develop a fatal CM‐like disease caused by CD8+ T cell‐mediated pathology. We found that treatment with interleukin‐15 complex (IL‐15C) prevented ECM, whereas IL‐2C treatment had no effect. IL‐15C‐expanded natural killer (NK) cells were necessary and sufficient for protection against ECM. IL‐15C treatment also decreased CD8+ T cell activation in the brain and prevented BBB breakdown without influencing parasite load. IL‐15C induced NK cells to express IL‐10, which was required for IL‐15C‐mediated protection against ECM. Finally, we show that ALT‐803, a modified human IL‐15C, mediates similar induction of IL‐10 in NK cells and protection against ECM. These data identify a regulatory role for cytokine‐stimulated NK cells in the prevention of a pathogenic immune response. Graphical Abstract Figure. No caption available. HighlightsIL‐15 complex (IL‐5C) treatment protects mice from experimental cerebral malaria (ECM)NK cell‐derived IL‐10 is required for IL‐15C‐mediated survival from ECMIL‐15C inhibits CD8+ T cell activation and cytokine production in the brainHuman NK cells also produce IL‐10 after cytokine stimulation In Brief NK cells can display both pro‐inflammatory and regulatory function, but their role in the pathogenesis of malaria is not fully understood. Burrack et al. demonstrate that IL‐15 complex (IL‐15C) therapy prevents mice from succumbing to experimental cerebral malaria (ECM). IL‐15C treatment stimulates NK cells to produce IL‐10, suppressing the pathogenic CD8+ T cell response during ECM.