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Granule-Dependent NK Cell Killing of Cryptococcus Requires Kinesin to Reposition the Cytolytic Machinery for Directed

Henry Ogbomo1, Martina Timm-McCann1, Tavish Barnes2

  • 1The Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB T2N 4N1, Canada.

Cell Reports
|September 13, 2018
PubMed

Insights

Natural killer (NK) cells fight fungal meningitis by moving toxic granules. Eg5-kinesin is crucial for NK cell granule movement and killing Cryptococcus, but not tumor cells.

Area of Science:

  • Immunology
  • Cell Biology
  • Microbiology

Background:

  • Cryptococcus causes fungal meningitis in immunocompromised individuals.
  • Natural killer (NK) cells are vital for host defense against Cryptococcus.
  • NK cells from HIV-infected patients exhibit impaired killing of Cryptococcus.

Purpose of the Study:

  • To investigate the mechanisms of cytolytic granule repositioning and polarization to the synapse in NK cells.
  • To understand why NK cells from HIV-infected patients fail to kill Cryptococcus.

Main Methods:

  • Live-cell imaging to observe microtubule and granule movements in NK cells upon encountering Cryptococcus.
  • Utilizing Eg5-kinesin inhibition to assess its role in granule polarization and NK cell function.
  • Comparing Eg5-kinesin's role in Cryptococcus killing versus tumor cell killing.

Main Results:

  • Eg5-kinesin binds to perforin-containing granules and is essential for their association with microtubules.
  • Eg5-kinesin inhibition disrupts dynein-dependent granule convergence to the microtubule-organizing center (MTOC).
  • Eg5-kinesin inhibition impairs NK cell synapse formation and suppresses Cryptococcus killing, but not tumor cell killing.

Conclusions:

  • Eg5-kinesin plays a critical, previously unrecognized role in initiating NK cell granule movement towards the MTOC.
  • This Eg5-kinesin-dependent mechanism is specific for microbial killing and distinct from NK cell tumor cytotoxicity.
  • Understanding this pathway offers insights into NK cell dysfunction in HIV and potential therapeutic targets for fungal meningitis.
Keywords:
Eg5-kinesinNK cell cytotoxicitydyneingranule congregationgranule convergencegranulysinmicrotubule organizing center polarizationperforin

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