Interleukin-15 Complex Treatment Protects Mice from Cerebral Malaria by Inducing Interleukin-10-Producing Natural Killer Cells

Immunity. 2018 Apr 17;48(4):760-772.e4. doi: 10.1016/j.immuni.2018.03.012. Epub 2018 Apr 3.

Abstract

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.

Keywords: CD8(+) T cells; IL-10; IL-15; NK cells; cerebral malaria; cytokine complexes; immunopathology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / pathology
  • Brain / immunology
  • Brain / pathology
  • CD8-Positive T-Lymphocytes / immunology
  • Interleukin-10 / biosynthesis
  • Interleukin-10 / immunology*
  • Interleukin-15 / immunology*
  • Killer Cells, Natural / immunology*
  • Lymphocyte Activation / immunology
  • Malaria, Cerebral / immunology*
  • Malaria, Cerebral / microbiology
  • Malaria, Cerebral / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Plasmodium berghei / immunology*
  • Proteins / pharmacology*
  • Recombinant Fusion Proteins

Substances

  • ALT-803
  • IL10 protein, mouse
  • Interleukin-15
  • Proteins
  • Recombinant Fusion Proteins
  • Interleukin-10