Natural killer (NK) cells were originally described in terms
of function in 1971 when Cudkowizc and Bennett observed that mice that had
received lethal irradiation were capable of rejecting allogeneic or parental
strain bone marrow cell (BMC) allografts.(1, 2) NK cells are of lymphoid origin
and are found in the peripheral blood, (constitute
approximately 10% of the lymphocytes in human peripheral blood), spleen, and BM, as
well as other tissues. They are radio-resistant, large, granular
lymphocytes that represent
an important arm of innate immunity and are thought to play a critical role in
the immune surveillance against tumors and virally infected cells.(3)They are
regulated by a number of receptors with opposite function that finely tune
potent effector functions such as cytolytic activity and production of
cytokines playing a major role in inflammation and regulation of both innate
and adaptive immune responses(4-9)

NK cells can
kill in a rapid manner and this NK cell-mediated cytotoxicity occurs primarily
through the perforin/granzyme-dependent pathway, although NK cells can also use
Fas ligand (FasL) and tumor necrosis factor related apoptosis inducing ligand
(TRAIL) to kill target cells (10). NK cells also have the ability to secrete a wide
range of cytokines upon activation (11) and these cytokines can either promote
or inhibit hematopoiesis, for example, GM-CSF and TGF-?, respectively(10-12).

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Cytokines also play a key role in the differentiation of NK
cells. Interleukin (IL)-2, IL-15, and IL-21, are capable of inducing proliferation
and activation of NK cells. However, only IL-15 and fms-like tyrosine kinase 3
(flt3) ligand have been shown to be critical for NK cell development and
maintenance (13-18). Stem cell factor (SCF) and fetal liver kinase ligand
(flk2L) have also been shown to be important in NK cell differentiation (19)

The function of NK cells is also mediated by cytokines.IL-12
and IFN-?/? exert potent stimulatory effects on NK cells, and IL-12 and IL-18
in combination is particularly effective in augmenting NK cell function (20, 21).
IL-2 has also been shown to significantly activate NK cells, and adoptive
immunotherapy of IL-2 activated NK cells after autologous BMT has been used in
patients with cancer with acceptable toxicities.(22) The predominant cytolytic targets
of NK cells are uncommon cells that have downregulated expression of class I MHC(MHC-I),
which is expressed on nearly every healthy cell of the body.(23) MHC-I loss is a fairly common
mechanism by which tumors and virus-infected cells can evade recognition by the
T-cell receptor of cytolytic T cells, and
NK cells.(24,25)


Recently, NK cells were officially classified as the
prototypical members of the group 1 innate lymphoid cells (ILCs), which are
defined by their capacity to secrete IFN-? but not type 2 cytokines (IL-4 and
IL-13), IL-17, or IL-22. Group 1 ILCs are thus distinct from group 2 ILCs,
which produce IL-13, and group 3 ILCs, which can produce IL-17, IL-22, or both.(26,27)
Human NK cells are classically defined as CD56+CD3- cells, distinguishing them from CD56+CD3+ cells, which consist of a mixed population of
NK-like T cells and antigen-experienced T cells that have upregulated several
NK cell markers.(28)

Two major subsets
of NK cells are found in human subjects that can be distinguished by their
levels of CD56 expression, namely CD56dim and CD56bright.(28) CD56dim
NK cells are fully mature, make up approximately 90% of the NK cells in
peripheral blood, and predominantly mediate cytotoxicity responses. In
contrast, CD56bright cells are more immature, make up approximately
5% to 15% of total NK cells, and have been considered primarily as cytokine
producers while playing a limited role in cytolytic responses. Although CD56bright
NK cells are more efficient at producing cytokines overall, the CD56dim
NK cells can also contribute significantly to early cytokine production because
they comprise a significantly greater fraction of the total NK cell pool and
can more rapidly secrete cytokines.(29-31)

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