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. 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.
Bibliographical noteFunding Information:
We thank Susan Pierce, PhD for parasites and advice. We thank Kristin Hogquist, PhD, and Thomas Morrison, PhD, for advice and critical review of the manuscript. This project was supported by a Grant-in-Aid from the University of Minnesota Office of the Vice President for Research ( 108127 to S.E.H.) and NIH grants R21-AI100088 (S.C.J. and S.E.H.), F32-AI120312-01 (K.S.B.), R56-NS094150 (A.J.J.), and T32-AI7425-19 (M.A.H.).
- CD8 T cells
- NK cells
- cerebral malaria
- cytokine complexes