Natural Killer (NK) cells are aptly named. They act like well-trained snipers, ready to target and destroy foreign cells at the drop of a hat.

They do not require prior sensitization, or exposure to foreign antigen, in order to kill. Instead, they have an innate, natural ability to recognize and destroy non-self cells.  

NK cells are broadly characterized as CD3- CD56+, and divided into two subsets, CD56dim and CD56bright, based upon density of CD56 expression. The dim subset has a relatively low density of CD56, whereas the bright subset has a high density.

CD56bright NK cells are more proliferative and have poor cytotoxic effector activity without stimulation. Conversely, the CD56dim NK cells express high levels of CD16 and are extremely cytotoxic even without stimulation.

CD16 induces cytokine expression and effector activity upon ligation, which is perhaps why the CD56dim NK cells are more cytotoxic than their “bright” counterparts.  

Regardless of their levels of CD56 expression, NK cells are believed to function via the “missing self hypothesis”.

The missing-self hypothesis postulates that the ability of NK cells to recognize and eliminate foreign cells is regulated by target cell expression of major histocompatibility complex class I molecules (MHC-I). The below image is adapted from Kumar and McNerney’s 2005 Nature Reviews Immunology article and illustrates at a high level  how the presence or absence of MHC-I molecules helps facilitate NK cell activity.


image outlining the missing-self and altered-self hypothesis of how nk cells function 


In summary, a target cell’s presentation of self-MHC is inversely correlated to NK cell destruction of the target cell.

For example, a self MHC-I expressing cell is recognized as “self” and is saved from destruction. A cell that has lost MHC-I expression, perhaps through viral infection, is recognized as “missing-self” and destroyed. Conversely, a cell expressing foreign MHC-I is recognized as “non-self” and is destroyed.     

In humans, the major histocompatibility complex is called the human leukocyte antigen (HLA). The inhibitory killer-cell immunoglobulin-like receptor (KIR) on the NK cell binds to the HLA molecules on the target cell. If there is a match between the NK cell KIR and target cell HLA, activation of inhibitory signals will save the target cell from destruction. Conversely, if there is a mismatch or missing HLA molecule, the inhibitory signal is not activated and the target cell is lysed.  

Initial thoughts were that NK cells were regulated solely by inhibitory factors, but further research over the years has added another prong to NK cell function called the “induced self”. The induced self hypothesis incorporates findings which support the presence of both activating and inhibiting receptors. For example, an infected or transformed cell will express stress-induced “self” proteins, which are recognized by KIR activating receptors, and the NK cell will be activated to kill the stressed cell.  

If we combine our understanding of NK cell function and the observation that many cancer cells have been observed to lose HLA expression, one can begin to see why NK cell activity is of interest to cancer researchers.

Imagine the possibilities if we are able to effectively exploit the natural activities of NK cells to specifically target and destroy cancer cells.  

image of nk cells targeting a cancer cell 

 While the potential of NK cells to be effective in immunotherapy is huge, there are clear challenges to overcome before we can fully realize that potential.

Three such challenges are the ability to control survival and proliferation after transplantation, migration to tumor sites, and targeting and destruction of specific cells.  

Carlsten and Childs recently published a review article in Frontiers in Immunology that nicely summarizes gene modification strategies to improve the ability of NK cells to persist and expand in-vivo, migrate to tumor sites, and enhance cancer cell cytotoxicity (see below figure).  


schematic describing current genetic modification strategies to optimize nk cells for use in immunotherapy 


The combination of advances in our understanding of the basic biology of NK cells, and enhanced technology for use in genetic manipulation are lighting the way to a promising arena for fighting cancer. But there is a lot of research still to be done before we can fully realize the potential of NK cells in immunotherapy.

Lonza is committed to supporting your NK cell research, which is why we offer research use NK cells as well as Nucleofector™ technology and NK cell Nucleofector™ transfection kits. Please contact Scientific Supportfor more information. 


Selected references:  

Present and future of allogeneic natural killer cell therapy  

Genetic manipulation of NK cells for cancer immunotherapy: Techniques and clinical implications  

NK cell-based immunotherapy for treating cancer: will it be promising?  

A new self: MHC-class-I-independent natural-killer-cell self-tolerance


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