The Importance of Natural Killer Immunity

By Dr Debby Hamilton, MD, MPH

Natural Killer (NK) cells are an important part of our innate immune response. Research is showing that NK cells play a greater role than previously thought in influencing other immune cells and the adaptive immune response. NK cell function can be upregulated or downregulated by cytokines and chemokines. Acute and chronic diseases with elevated inflammation downregulate NK cell activity, decreasing the body’s ability to fight infections and cancer.

What are natural killer cells?

Natural Killer (NK) cells are derived from lymphocytes in the same lineage as B and T cells. They are part of the first line of immune defence. By releasing inflammatory cytokines stored as intracellular granules, they assist in removing transformed or infected cells. More recent research has shown that NK cells can also play a role in antigen specificity and immune memory responses.¹ Natural Killer cells are regulated by the balance of inhibitory and activating signals such as cytokines and chemokines that bind to receptors.² Control of the interactions between NK cells and other cells of the immune system is driven by the transcription factor STAT3.³

What are the primary functions of natural killer cells?

Natural Killer cells are critical for first-line immune defence against viral infections.⁴ People with congenital natural killer cell deficiency have an increase in viral infections. The Natural Killer cells use multiple mechanisms to kill virally infected cells including engagement of death receptors and release of cytokines.⁴ Healthy cells inhibit natural killer cell activation by having the major histocompatibility complex class-1 (MHC-1) expressed on the cell. In contrast, decreased expression of the MHC-1 promotes the killing of virally infected cells by the NK cells.³ NK cells are also the first-line defence for tumor cells. This defence helps against tumor initiation, growth of the tumor, and metastasis.² NK cells, in a similar manner for virally infected cells, will degranulate cytotoxic chemicals and work through death receptor pathways.² These cells are also able to promote anti-tumor adaptive t-cell immunity.²

What conditions have lower natural killer cell function?

Many chronic diseases, such as cardiovascular diseases and obesity, have lower natural killer cell function.⁵ Advanced age is also associated with a decrease in immune function including lower natural killer cell function which is part of the reason for increased vulnerability to infections and cancer seen in the aging population.⁶ People with chronic diseases are at an increased risk of viral infections in part to this decrease in immune function. This has been seen with COVID-19 infections also. People with more severe COVID have lower natural killer cell function.^6,7 One of the underlying factors in chronic disease and aging is inflammation. Inflammation is associated with an increase in inflammatory cytokines, such as TGF-B. Elevated TGF-B binds and downregulates natural killer cell function, decreasing the body’s ability to fight a viral infection or inhibit cancer cell growth.^6,7 Elevated TGF-B has been found in people with more severe COVID-19.^6,7

How do you support natural killer cell function? Transfer factors, probiotics, glutathione

Many different immune and inflammation supplements have been found to help increase NK function. Probiotic bacteria in the intestine are an important part of our immune system. They are known immune modulators that can support NK cell function in the digestive tract. They help activate the NK cells through the secretion of immune factors such as interferon-y.⁸ Transfer factors are another key component of our immune system. They are protein cell signalling molecules released from T cells in a similar role to antibodies released from B cells. Transfer factors are naturally present in colostrum and support the activation of NK cells and Th1 cell-mediated immunity.⁹ They can be isolated and used as an immune supplement that can help target NK cell activation. Research has demonstrated that the antioxidant vitamins C and E can positively impact immune stimulation of NK cells.¹⁰ Glutathione is another antioxidant that has been shown to increase NK cell function.¹¹ Antioxidants help to decrease inflammation by decreasing oxidative stress. By decreasing inflammation, they may decrease the negative feedback by cytokines on NK cell function. Natural anti-inflammatory herbs such as curcumin and resveratrol also support NK cell function by decreasing the release of pro-inflammatory cytokines.^12,13 Summary Decreased NK cell function is common in many conditions with inflammation. Decreasing inflammation and supporting NK cell function are important for overall immune health. This can be done safely with anti-inflammatory herbs, antioxidants, probiotics, and/or transfer factors.

References

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2. Smythe, M., Hayakawa, Y., Takeda, K. et al. New aspects of natural-killer-cell surveillance and therapy of cancer. Nat Rev Cancer 2, 850–861 (2002).

3. Cacalano NA. Regulation of Natural Killer Cell Function by STAT3. Front. Immunol., 11 April 2016.

4. Van Erp EA, van Kampen MR, van Kasteren PB, de Wit J. Viral Infection of Human Natural Killer Cells. Viruses. 2019;11(3):243.

5. Jabir NR. et al. Reduction in CD16/CD56 and CD/16/ CD3/CD56 natural killer cells in cardiovascular disease. Jr. of Mol And Cellular Immunology. 2017.

6. Van Eeden C, Khan L, Osman MS, Cohen Tervaert JW. Natural Killer Cell Dysfunction and Its Role in COVID-19. International Journal of Molecular Sciences. 2020; 21(17):6351.

7. Narni-Mancinellei E, Vivier E. Clues that natural killer cells help to control COVID. Nature. 2021.

8. Aziz N, Bonavida B. Activation of Natural Killer Cells by Probiotics. For Immunopathol Dis Therap. 2016;7(1- 2):41-55.

9. Krishnaveni M., et al. A review on transfer factor an immune modulator, Drug Invention Today. 2013. Vol 5 (2): 153-156.

10. Grudzien M, Rapak A. Effect of Natural Compounds on NK Cell Activation. J Immunol Res. 2018;2018:4868417.

11. Sinha R. et al. Oral supplementation with liposomal glutathione elevates body stores and markers of immune function. Eur. Jr. of Clin Nut. 2017, 1-7.

12. Lee HH, Cho H. Improved anti-cancer effect of curcumin on breast cancer cells by increasing the activity of natural killer cells. Jr. of Micro and Biotech. 2018.

13. Leischner, C., Burkard, M., Pfeiffer, M.M. et al. Nutritional immunology: function of natural killer cells and their modulation by resveratrol for cancer prevention and treatment. Nutr J 15, 47 (2015).