Kanikah Mehndiratta, MSc, University of Glasgow
The human body encounters different types of pathogenic microbes and stressful events that can cause infection and convert normal cells into tumour cells. Our immune system has the ability to recognize and potentially eradicate such tumorous cells or any other cells working aberrantly. Mainly it’s the killer lymphocytes that prove cytotoxic and provide protection against them. How they stay protected against their own defence mechanisms when in close combat with targeted cells has been an interesting area of research for years. A recent study published in the PLOS Biology journal discusses the survival advantages of natural killer (NK) cells in comparison to their targets, particularly via their high lipid order presynaptic membrane.
Natural killer cells against infection:
NK cells act against target cells by secreting perforin at a specialized interface between the cell and its target. The interface is basically a lytic immunological synaptic cleft where the protein lies in close range to both the cells during their hydrophobic interaction. The protein creates pores in the plasma membrane of the target infectious cells which allows for the delivery of proapoptotic enzymes. The enzymes can damage the target cells, but the NK cells stay protected from the activity of the enzymes. There is definitely a mechanism that confers changes to the NK cell to confer protection against such autolysis.
The research discusses degranulation of the lytic granules or the perforin-containing organelles as an enhancer of presynaptic membrane packing and associated protection. The highly ordered and endogenously densely packed lipid membranes in the pre-synaptic phase increase lipid packing upon the formation of the synapse. This protection is specifically enhanced at the site where the NK cells would be the most exposed to perforin.
Research strategy adopted:
NK cells were treated with 7-ketocholesterol in-vitro. This resulted in a reduction in lipid packing which after degranulation, resulted in increased susceptibility to perforin mediated autolysis. The study showed induction of death of NK cells during cytolytic activities. The time frame of the cytotoxic assay was about 4 hours, though target cell killing can happen much earlier in the time frame. NK cells that were freshly isolated from an ex-vivo human were used as a reference to compare the effect of treatment to the actual scenario. Techniques such as high-resolution lipidomics and imaging were used to check for such dense arrangement of the lipid granule membrane. The approach also focused on the coalescence of the membrane domains, also called as rafts for causing inhibition to the binding of perforin to the NK cells.
Conclusion:
The study concludes that degranulation enhances packaging within the presynaptic membrane of the lipo-granules. This acts as a defense mechanism of Natural killer cells against their own autolytic enzymes via local-ordered lipid shields. The study additionally found a perforin-resistant breast cancer cell line that is able to evade lytic activity of the NK cells because of a postsynaptic membrane that is densely packed. The disruption of such packaging led to switching into an NK-susceptible state that provides scope for cytotoxic cell-based therapies against breast cancer.
Also read: A study of mortality from Alzheimer’s disease & other dementias
References:
1. Li, Y., & Orange, J. S. (2021). Degranulation enhances presynaptic membrane packing, which protects NK cells from perforin-mediated autolysis. PLOS Biology, 19(8), e3001328. https://doi.org/10.1371/journal.pbio.3001328
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Author info:
Kanikah Mehndiratta is an avid researcher in the field of Genetics with a background in Biotechnology. She is a postgraduate from the University of Glasgow in their Medical Genetics and Genomics program. Currently, based in Chandigarh as a scientific writer, she involves herself mainly in projects related to neurological disorders. Outside of academics, she likes to read novels, travel and is involved in volunteer work mostly.
LinkedIn profile- https://www.linkedin.com/in/kanikah-mehndiratta-301830171
Other articles-
1. https://bioxone.in/news/worldnews/pre-exposure-prophylaxis-trajectories-for-targeting-aids/
2. https://bioxone.in/news/worldnews/crispr-cas9-for-disease-resistance-in-salmon/
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