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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.
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
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.
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.
induces cytokine expression and effector activity upon ligation, which is
perhaps why the CD56dim NK cells are more cytotoxic than their
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.
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.
possibilities if we are able to effectively exploit the natural activities of
NK cells to specifically target and destroy cancer cells.
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
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).
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
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
Present and future of allogeneic natural killer cell therapy http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453480/
Genetic manipulation of NK cells for cancer immunotherapy: Techniques
and clinical implications http://www.ncbi.nlm.nih.gov/pubmed/26113846
NK cell-based immunotherapy for treating cancer: will it be promising? http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065623/
A new self: MHC-class-I-independent natural-killer-cell self-tolerance http://www.ncbi.nlm.nih.gov/pubmed/15841099
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