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Human NK cells kill resting but not activated microglia via NKG2D- and NKp46-mediated recognition

Anna Lünemann1, Jan D Lünemann, Susanne Roberts

  • 1Laboratory of Viral Immunobiology, Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10065, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|October 23, 2008
PubMed

Insights

Human NK cells eliminate resting microglia in the brain. This NK cell activity, dependent on cell contact and specific receptors, may restrict immune responses in the central nervous system (CNS).

Area of Science:

  • Neuroimmunology
  • Cellular immunology
  • Innate immunity

Background:

  • Microglia, the CNS's resident immune cells, must tightly regulate inflammatory responses to prevent damage.
  • Natural Killer (NK) cells infiltrate the CNS during brain injury, but their precise role and mechanisms remain unclear.

Purpose of the Study:

  • To investigate if and how human NK cells kill resting and activated human microglia in vitro.
  • To elucidate the mechanisms underlying NK cell-mediated microglial cytotoxicity.

Main Methods:

  • Co-culture of IL-2-activated human NK cells with resting and activated human microglia.
  • Assessment of cell-contact-dependent killing.
  • Analysis of NK cell synapse formation and perforin polarization.
  • Use of antibody-mediated blockade of NKG2D and NKp46 receptors.
  • Investigation of MHC class I expression's role in microglial protection.

Main Results:

  • Activated human NK cells efficiently killed both resting and activated human microglia in a cell-contact-dependent manner.
  • NK cells formed synapses with microglia, polarizing perforin to the interface.
  • Blockade of NKG2D and NKp46 receptors abrogated NK cell-mediated microglial killing.
  • Increased MHC class I expression protected microglia from NK cell killing, while MHC class I blockade enhanced it.

Conclusions:

  • Brain-infiltrating NK cells may restrict immune responses in the human CNS by eliminating resting microglia.
  • NK cell-mediated killing of microglia involves specific receptors (NKG2D, NKp46) and is modulated by MHC class I expression.

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