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

Kristina S Burrack1, Matthew A Huggins2, Emily Taras3

  • 1Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55414, USA.

Immunity
|April 8, 2018
PubMed

Insights

Interleukin-15 complex (IL-15C) prevents experimental cerebral malaria (ECM) by activating natural killer (NK) cells. These IL-15C-stimulated NK cells produce IL-10, protecting the blood-brain barrier and preventing fatal disease.

Area of Science:

  • Immunology
  • Neuroscience
  • Infectious Diseases

Background:

  • Cerebral malaria (CM) is a severe complication of Plasmodium infection, characterized by blood-brain barrier (BBB) disruption and white blood cell infiltration.
  • Experimental cerebral malaria (ECM) in mice, induced by Plasmodium berghei ANKA, serves as a model for CM pathology, driven by CD8+ T cell responses.

Purpose of the Study:

  • To investigate the therapeutic potential of cytokine complexes in preventing ECM.
  • To elucidate the cellular and molecular mechanisms underlying protection against ECM.

Main Methods:

  • Treatment of mice with interleukin-15 complex (IL-15C) or interleukin-2 complex (IL-2C) during ECM induction.
  • Assessment of ECM development, parasite load, CD8+ T cell activation, and BBB integrity.
  • Analysis of natural killer (NK) cell populations and their cytokine production (IL-10).
  • Evaluation of ALT-803, a modified human IL-15C, for its therapeutic efficacy.

Main Results:

  • IL-15C treatment effectively prevented ECM, while IL-2C had no protective effect.
  • IL-15C-expanded NK cells were identified as crucial mediators of protection, being both necessary and sufficient.
  • IL-15C treatment reduced CD8+ T cell activation in the brain and preserved BBB integrity without affecting parasite levels.
  • Protection mediated by IL-15C was dependent on NK cell production of IL-10.
  • ALT-803, a human IL-15C analog, replicated the protective effects of IL-15C, including IL-10 induction in NK cells.

Conclusions:

  • Cytokine-stimulated NK cells play a regulatory role in preventing pathogenic immune responses during cerebral malaria.
  • IL-15C represents a promising therapeutic strategy for preventing ECM by modulating NK cell function and IL-10 production.
  • Targeting NK cell-mediated immunity offers a novel approach to combatting severe malaria complications.
Keywords:
CD8(+) T cellsIL-10IL-15NK cellscerebral malariacytokine complexesimmunopathology

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