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NK cells switch from granzyme B to death receptor-mediated cytotoxicity during serial killing

Isabel Prager1, Clarissa Liesche2, Hanna van Ooijen3

  • 1Department for Immunology, Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund, Dortmund, Germany.

The Journal of Experimental Medicine
|July 5, 2019
PubMed

Insights

Natural killer (NK) cells shift from granzyme B (GrzB) to death receptor pathways during serial killing of tumor cells. This switch is regulated by perforin and CD95L, impacting NK cell cytotoxicity.

Area of Science:

  • Immunology
  • Cell Biology
  • Cancer Research

Background:

  • Natural killer (NK) cells are crucial for innate immunity, eliminating infected and cancerous cells.
  • NK cell cytotoxicity is mediated by cytotoxic granules (containing granzyme B [GrzB]) and death receptor pathways (e.g., involving caspase cascades).
  • The coordinated regulation of these distinct NK cell killing mechanisms remains incompletely understood.

Purpose of the Study:

  • To investigate the interplay between GrzB and death receptor pathways during NK cell serial killing.
  • To elucidate the mechanisms controlling the switch between these cytotoxic pathways in NK cells.

Main Methods:

  • Simultaneous measurement of GrzB and caspase-8 activity in tumor cells upon human NK cell contact.
  • Assessment of NK cell cytotoxic function with and without perforin or CD95 expression on target cells.

Main Results:

  • NK cells demonstrated a switch from rapid GrzB-mediated killing to slower death receptor-mediated killing during serial tumor cell encounters.
  • NK cell-target cell contact led to decreased intracellular GrzB and perforin, and increased surface CD95L, indicating pathway regulation.
  • Perforin deficiency impaired GrzB-mediated serial killing, while CD95 absence on targets did not affect GrzB killing.

Conclusions:

  • NK cell serial killing involves a dynamic switch between GrzB and death receptor pathways.
  • Perforin is essential for GrzB-mediated serial killing, whereas CD95 engagement on targets is not required for this pathway.
  • These findings reveal differential regulation of GrzB and death receptor cytotoxicity during NK cell effector functions.

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