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

Kristina S. Burrack, Matthew A. Huggins, Emily Taras, Philip Dougherty, Christine M. Henzler, Rendong Yang, Sarah Alter, Emily K. Jeng, Hing C. Wong, Martin Felices, Frank Cichocki, Jeffrey S. Miller, Geoffrey T. Hart, Aaron J. Johnson, Stephen C. Jameson, Sara E. Hamilton

Research output: Contribution to journalArticle

10 Citations (Scopus)

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. 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.

Original languageEnglish (US)
JournalImmunity
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Cerebral Malaria
Interleukin-15
Natural Killer Cells
Interleukin-10
Blood-Brain Barrier
T-Lymphocytes
Malaria
Parasite Load
Plasmodium berghei
Cytoprotection
Leukocytes
Erythrocytes
Pathology
Cytokines
Brain

Keywords

  • CD8 T cells
  • cerebral malaria
  • cytokine complexes
  • IL-10
  • IL-15
  • immunopathology
  • NK cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Burrack, K. S., Huggins, M. A., Taras, E., Dougherty, P., Henzler, C. M., Yang, R., ... Hamilton, S. E. (Accepted/In press). Interleukin-15 Complex Treatment Protects Mice from Cerebral Malaria by Inducing Interleukin-10-Producing Natural Killer Cells. Immunity. https://doi.org/10.1016/j.immuni.2018.03.012

Interleukin-15 Complex Treatment Protects Mice from Cerebral Malaria by Inducing Interleukin-10-Producing Natural Killer Cells. / Burrack, Kristina S.; Huggins, Matthew A.; Taras, Emily; Dougherty, Philip; Henzler, Christine M.; Yang, Rendong; Alter, Sarah; Jeng, Emily K.; Wong, Hing C.; Felices, Martin; Cichocki, Frank; Miller, Jeffrey S.; Hart, Geoffrey T.; Johnson, Aaron J.; Jameson, Stephen C.; Hamilton, Sara E.

In: Immunity, 01.01.2018.

Research output: Contribution to journalArticle

Burrack, KS, Huggins, MA, Taras, E, Dougherty, P, Henzler, CM, Yang, R, Alter, S, Jeng, EK, Wong, HC, Felices, M, Cichocki, F, Miller, JS, Hart, GT, Johnson, AJ, Jameson, SC & Hamilton, SE 2018, 'Interleukin-15 Complex Treatment Protects Mice from Cerebral Malaria by Inducing Interleukin-10-Producing Natural Killer Cells', Immunity. https://doi.org/10.1016/j.immuni.2018.03.012
Burrack, Kristina S. ; Huggins, Matthew A. ; Taras, Emily ; Dougherty, Philip ; Henzler, Christine M. ; Yang, Rendong ; Alter, Sarah ; Jeng, Emily K. ; Wong, Hing C. ; Felices, Martin ; Cichocki, Frank ; Miller, Jeffrey S. ; Hart, Geoffrey T. ; Johnson, Aaron J. ; Jameson, Stephen C. ; Hamilton, Sara E. / Interleukin-15 Complex Treatment Protects Mice from Cerebral Malaria by Inducing Interleukin-10-Producing Natural Killer Cells. In: Immunity. 2018.
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AU - Yang, Rendong

AU - Alter, Sarah

AU - Jeng, Emily K.

AU - Wong, Hing C.

AU - Felices, Martin

AU - Cichocki, Frank

AU - Miller, Jeffrey S.

AU - Hart, Geoffrey T.

AU - Johnson, Aaron J.

AU - Jameson, Stephen C.

AU - Hamilton, Sara E.

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AB - 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.

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