Natural activation (11) and these cytokines can either

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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The
identification of MHC class I-specific inhibitory and activating receptors in
addition to non-MHC class I specific activating and inhibitory receptors has
grown substantially in the two past decades. This has led to a tremendously complex
set of receptors responsible for innate recognition of foreign, abnormal, or
virally infected cells by NK cells, and these receptors have become relevant
with respect to allogeneic BMT and malignant cancer therapies.(1) The first
class of MHC class I-specific receptors was identified in mouse and is termed
Ly49. In any given mouse, an NK cell population can express a variable
combination of the 20 or more Ly49 receptors characterized. Some of these
receptors have different affinities for the different MHC class I
molecules.(2,3)

The next
class of receptors are the killer cell Ig-like receptors (KIRs) which
specifically recognize groups of HLA-C (p58 or KIR2DL1-KIR3DL3)(4-7), HLA-B
(p70 or KIR3DL1) and HLA-A alleles (p140) (8-13) Both the Ly49 and KIR
multi-receptor families contain members that have either activating or
inhibitory action.(14)

Another class
of MHC class I-specific receptors expressed both in humans and in mice is
comprised of the C-type lectin molecule CD94, which is covalently associated
with a member of the NKG2 family. Like Ly49 and KIR receptors, these receptors
also have been shown to exert inhibitory (NKG2A or NKG2B) or activating (NKG2C)
signals upon binding Qa-1b (mouse) or non-classical HLA-E (human) molecules on
targets (15-18).

NK cells also
have Ig-like transcript (ILT) receptors that interact with HLA-G (to protect
the fetus and placenta from rejection)(19). Another group of NK cell receptors
comes from a more diverse family of receptors of NK-cell-specific Ig-like
molecules that are known as natural cytotoxicity receptors, or NCRs. NCRs
include NKp30, NKp46, and NKp44 as well as NKG2D. NKG2D is a member of the NKG2
family expressed by NK cells and cytotoxic lymphocytes (CTLs) (20-23). most NK
cells can express the Fc?RIII (CD16) molecule, which recognizes the Fc
component of bound Ig molecules and initiates cytolysis by the antibody
dependent cellular cytotoxicity (ADCC) pathway (24), thus giving the NK cell
another method of target recognition.(1)

Finally,
natural killer cells have 5 main categories of cell surface receptors. Activating  receptors (e.g. CD16, NKp46, NKG2D, NKG2C,
KIR-S, Ly9), Inhibitory receptors (e.g. KIR-L, NKG2A), chemotactic receptors
(e.g. CCR2,CCR5,CXCR1,CXCR4,CXCR6), Cytokine receptors(e.g.  IL-1R, IL-15R,IL-18R), Adhesion
receptors(e.g. ?1 integrins).

Allogeneic bone
marrow transplantation (BMT) has proven to be an effective treatment for
hematologic malignancies and some solid tumors.(1) However, the high incidence
of graft-versus-host disease (GVHD) as a complication of this treatment has
limited the overall effectiveness of BMT.(2) GVHD is mediated by the activation
and proliferation of alloreactive T cells leading to tissue damage in the host,
primarily in the gastrointestinal tract, liver, and skin (3) causing
significant morbidity and mortality.

One of the
major challenges of allo-Stem Cell Transplantation(SCT) is to reduce the
incidence and severity of GVHD while boosting the graft-versus-leukemia (GVL)
effect. In the setting of allo-SCT, the reconstitution of natural killer (NK)
cells is of notable interest due to their known capability to induce GVL
without GVHD.(4) Studies of the role of NK cells in
bone marrow engraftment demonstrated that host NK cells persisting after
conditioning can contribute to graft rejection (5) while donor NK cells can promote hematopoietic
engraftment (6).

The first study
suggesting a relationship between NK cells and GvHD development was reported by
Lopez and coworkers from the Sloan Kettering Cancer Center showing a
significant association between GvHD development and pre-transplant levels of
NK cell activity, as measured by cytotoxic assays performed using herpes
simplex virus type 1-infected fibroblast as target cells, in peripheral blood
of a small and heterogeneous cohort of 13 patients undergoing different protocols
of HCT.(7) Livnat et
al. (8) and
Dokhelar et al. (9) addressed the same issue assessing NK cell activity
against the K562 leukemic cell line both before and after hematopoietic
cell transplantation (HCT) and obtained contradictory
results finding either no relationship (8) or a positive association (9) between early post transplant NK
cell activity and GvHD development. In 2015
Jacobs B. and et al could demonstrate that NK cells gain cytotoxic and
cytokine producing functions early during hematopoietic immune reconstitution
following autologous SCT.(10) In addition to clinical studies, it has been
shown in animal models that IL-2-activated NK cells may efficiently prevent or
even reduce GVHD without any adverse impact on their important GVL effect.(11-13)

After
chemotherapy or hematopoietic stem cell transplantation, NK cells are the first
lymphoid cells to recover (14,15). Surprisingly, such postgrafting regeneration
of NK cells does not cause clinical graft-versus-host disease (GVHD); this has
led to the conclusion that normal nonhematopoietic tissues lack ligands able to
activate NK cell lysis.(16)

The concept of
an NK-mediated regulatory function is also supported by the observation that a
higher number of bone marrow NK cells has been associated with a decreased
incidence of chronic GVHD after HLA identical sibling bone marrow transplants
in human.(17)Researches in 2002 and 2004 showed that this regulatory function
can be indirect, through the interplay and molecular crosstalk with dendritic
cells (DCs) (18,19). On the one hand, DCs can prime, further the activation of,
augment the expansion of, and enhance the activities of NK cells through the
production of cytokines such as IL-2, IL-12, IL-15, IFN-a/b, and TNFa.(16) The
regulatory function of NK cells on adaptive immuneresponses appears also to be
mediated through direct lysis of activated T cells (20,21). This pathway has
been postulated to play an important role in the generation of memory T cell repertoire.
Several recent observations suggest that certain subpopulations of NK cells
promote allograft tolerance via a cytolysis-dependent regulatory pathway (22–24).
However, little is known about the effects of NK cells on donor T cells after
BMT. In 2010, Magali Noval Rivas et al showed that NK cells can regulate
chronic GVHD by limiting recipient minor histocompatibility Ag (mHA)-driven
proliferation of donor CD4+ T cells.(16)

According to studies by scientists, the relationship between NK Cell and GVHD can be generally described in two ways: firstly, Nk Cell cytotoxic functions and GvHD prevention: NK cells can suppress GvHD development through their cytotoxic function either directly, by depleting activated alloreactive T cells, or indirectly, by depleting APC and preventing T cell stimulation,T cell killing by NK cells appears to be dependent on both perforin production (25,26,27) and FAS-mediated induction of apoptosis (26, 28, 29),and secondary Nk Cell cytokine production and GvHD induction: Although it is unclear if NK cells production of immunesuppressive

cytokines can
prevent GvHD, it is established that pro-inflammatory cytokine production by NK
cells can contribute to GvHD development. Xun et al. showed In a xenogeneic
model that in vitro interleukin-2 (IL-2)-activated human NK cells producing
interferon-?(IFN-?) and tumor necrosis factor-?(TNF-?) were able to induce
acute GVHD upon transfer into SCID mice (30, 31) What is now important about NK cells and its impact on GVHD is that
researchers are looking for new ways to reduce GVHD with the help of these
cells, which we will continue to mention these
activities.

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)