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Published on: February 22, 2020
Molecular regulation of the plasma membrane-proximal cellular steps involved in NK cell cytolytic function
Prasad V Phatarpekar1, Daniel D Billadeau2
1Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Abstract:
Natural killer (NK) cells, cytolytic lymphocytes of the innate immune system, play a crucial role in the immune response against infection and cancer. NK cells kill target cells through exocytosis of lytic granules that contain cytotoxic proteins, such as perforin and granzymes. Formation of a functional immune synapse, i.e. the interface between the NK cell and its target cell enhances lysis through accumulation of polymerized F-actin at the NK cell synapse, leading to convergence of lytic granules to the microtubule organizing center (MTOC) and its subsequent polarization along microtubules to deliver the lytic granules to the synapse. In this review, we focus on the molecular mechanisms regulating the cellular processes that occur after the lytic granules are delivered to the cytotoxic synapse. We outline how - once near the synapse - the granules traverse the clearings created by F-actin remodeling to dock, tether and fuse with the plasma membrane in order to secrete their lytic content into the synaptic cleft through exocytosis. Further emphasis is given to the role of Ca2+ mobilization during degranulation and, whenever applicable, we compare these mechanisms in NK cells and cytotoxic T lymphocytes (CTLs) as adaptive immune system effectors.
Insights
Natural killer (NK) cells eliminate targets via cytotoxic granules. This review details how these granules move to the immune synapse and release their contents through exocytosis, crucial for innate immunity.
Area of Science:
- Immunology
- Cell Biology
Background:
- Natural killer (NK) cells are key players in the innate immune system, combating infections and cancer.
- NK cell-mediated cytotoxicity relies on releasing cytotoxic proteins from granules into target cells.
- Formation of an immune synapse is essential for efficient NK cell killing.
Purpose of the Study:
- To review the molecular mechanisms governing cytotoxic granule exocytosis at the NK cell immune synapse.
- To elucidate the steps involved in granule docking, tethering, and fusion post-synaptic delivery.
- To highlight the role of calcium mobilization in NK cell degranulation.
Main Methods:
- Literature review focusing on molecular mechanisms of granule exocytosis.
- Analysis of cellular processes at the immune synapse.
- Comparison of NK cell and cytotoxic T lymphocyte (CTL) degranulation.
Main Results:
- Granules move to the synapse, traverse actin-cleared zones, and dock/tether to the plasma membrane.
- Exocytosis releases granule contents into the synaptic cleft.
- Calcium (Ca2+) influx is critical for triggering degranulation.
Conclusions:
- Understanding NK cell degranulation mechanisms is vital for immune response research.
- These processes are conserved but have distinct features compared to CTLs.
- Further research into granule trafficking and fusion can inform cancer and infection therapies.
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