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Shedding of CD16 disassembles the NK cell immune synapse and boosts serial engagement of target cells

Katja Srpan1, Ashley Ambrose1, Alexandros Karampatzakis1

  • 1The Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, UK.

The Journal of Cell Biology
|July 4, 2018
PubMed

Insights

Natural Killer (NK) cells secrete less perforin after repeated CD16 receptor activation. However, NKG2D receptor activation restores this secretion, suggesting CD16 shedding positively impacts immune responses by enhancing NK cell motility and serial target engagement.

Area of Science:

  • Immunology
  • Cell Biology

Background:

  • Natural Killer (NK) cells are crucial for innate immunity, mediating cytolytic killing of infected or cancerous cells.
  • NK cells sequentially engage and eliminate multiple target cells through perforin delivery.

Purpose of the Study:

  • To investigate the impact of sequential activation via different receptors (CD16 and NKG2D) on NK cell degranulation and perforin secretion.
  • To elucidate the role of CD16 shedding in modulating NK cell function and immune synapse dynamics.

Main Methods:

  • Microscopy was used to visualize degranulation from individual NK cells.
  • Sequential activation of NK cells via CD16 and NKG2D receptors was performed.
  • Pharmacological inhibitors and genetically modified NK cells (non-cleavable CD16) were employed.

Main Results:

  • Repeated CD16 activation decreased perforin secretion, which was restored by NKG2D activation.
  • Repeated NKG2D activation decreased perforin secretion, not rescued by CD16 activation.
  • CD16 shedding, triggered by cellular activation, was identified as a key mechanism.
  • CD16 shedding increased NK cell motility, facilitated target cell detachment, and promoted survival, enhancing serial engagement.

Conclusions:

  • Sequential activation via CD16 and NKG2D receptors differentially regulates NK cell degranulation.
  • CD16 shedding plays a counterintuitive, positive role in NK cell-mediated immune responses by enhancing motility and serial killing.
  • Understanding CD16 shedding mechanisms can inform strategies to boost anti-viral and anti-tumor immunity.

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