Natural killer (NK) cells were originally described in termsof function in 1971 when Cudkowizc and Bennett observed that mice that hadreceived lethal irradiation were capable of rejecting allogeneic or parentalstrain bone marrow cell (BMC) allografts.(1, 2) NK cells are of lymphoid originand are found in the peripheral blood, (constituteapproximately 10% of the lymphocytes in human peripheral blood), spleen, and BM, aswell as other tissues.
They are radio-resistant, large, granularlymphocytes that representan important arm of innate immunity and are thought to play a critical role inthe immune surveillance against tumors and virally infected cells.(3)They areregulated by a number of receptors with opposite function that finely tunepotent effector functions such as cytolytic activity and production ofcytokines playing a major role in inflammation and regulation of both innateand adaptive immune responses(4-9) NK cells cankill in a rapid manner and this NK cell-mediated cytotoxicity occurs primarilythrough the perforin/granzyme-dependent pathway, although NK cells can also useFas 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 widerange of cytokines upon activation (11) and these cytokines can either promoteor inhibit hematopoiesis, for example, GM-CSF and TGF-?, respectively(10-12).
Theidentification of MHC class I-specific inhibitory and activating receptors inaddition to non-MHC class I specific activating and inhibitory receptors hasgrown substantially in the two past decades. This has led to a tremendously complexset of receptors responsible for innate recognition of foreign, abnormal, orvirally infected cells by NK cells, and these receptors have become relevantwith respect to allogeneic BMT and malignant cancer therapies.(1) The firstclass of MHC class I-specific receptors was identified in mouse and is termedLy49. In any given mouse, an NK cell population can express a variablecombination of the 20 or more Ly49 receptors characterized. Some of thesereceptors have different affinities for the different MHC class Imolecules.(2,3)The nextclass of receptors are the killer cell Ig-like receptors (KIRs) whichspecifically 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 KIRmulti-receptor families contain members that have either activating orinhibitory action.
(14)Another classof MHC class I-specific receptors expressed both in humans and in mice iscomprised of the C-type lectin molecule CD94, which is covalently associatedwith a member of the NKG2 family. Like Ly49 and KIR receptors, these receptorsalso 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 ontargets (15-18).NK cells alsohave Ig-like transcript (ILT) receptors that interact with HLA-G (to protectthe fetus and placenta from rejection)(19). Another group of NK cell receptorscomes from a more diverse family of receptors of NK-cell-specific Ig-likemolecules that are known as natural cytotoxicity receptors, or NCRs. NCRsinclude NKp30, NKp46, and NKp44 as well as NKG2D. NKG2D is a member of the NKG2family expressed by NK cells and cytotoxic lymphocytes (CTLs) (20-23).
most NKcells can express the Fc?RIII (CD16) molecule, which recognizes the Fccomponent of bound Ig molecules and initiates cytolysis by the antibodydependent cellular cytotoxicity (ADCC) pathway (24), thus giving the NK cellanother 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), Adhesionreceptors(e.g. ?1 integrins).Allogeneic bonemarrow transplantation (BMT) has proven to be an effective treatment forhematologic malignancies and some solid tumors.
(1) However, the high incidenceof graft-versus-host disease (GVHD) as a complication of this treatment haslimited the overall effectiveness of BMT.(2) GVHD is mediated by the activationand proliferation of alloreactive T cells leading to tissue damage in the host,primarily in the gastrointestinal tract, liver, and skin (3) causingsignificant morbidity and mortality.One of themajor challenges of allo-Stem Cell Transplantation(SCT) is to reduce theincidence 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 GVLwithout GVHD.(4) Studies of the role of NK cells inbone marrow engraftment demonstrated that host NK cells persisting afterconditioning can contribute to graft rejection (5) while donor NK cells can promote hematopoieticengraftment (6).The first studysuggesting a relationship between NK cells and GvHD development was reported byLopez and coworkers from the Sloan Kettering Cancer Center showing asignificant association between GvHD development and pre-transplant levels ofNK cell activity, as measured by cytotoxic assays performed using herpessimplex virus type 1-infected fibroblast as target cells, in peripheral bloodof a small and heterogeneous cohort of 13 patients undergoing different protocolsof HCT.(7) Livnat etal. (8) andDokhelar et al.
(9) addressed the same issue assessing NK cell activityagainst the K562 leukemic cell line both before and after hematopoieticcell transplantation (HCT) and obtained contradictoryresults finding either no relationship (8) or a positive association (9) between early post transplant NKcell activity and GvHD development. In 2015Jacobs B. and et al could demonstrate that NK cells gain cytotoxic andcytokine producing functions early during hematopoietic immune reconstitutionfollowing autologous SCT.
(10) In addition to clinical studies, it has beenshown in animal models that IL-2-activated NK cells may efficiently prevent oreven reduce GVHD without any adverse impact on their important GVL effect.(11-13)Afterchemotherapy or hematopoietic stem cell transplantation, NK cells are the firstlymphoid cells to recover (14,15). Surprisingly, such postgrafting regenerationof NK cells does not cause clinical graft-versus-host disease (GVHD); this hasled to the conclusion that normal nonhematopoietic tissues lack ligands able toactivate NK cell lysis.(16)The concept ofan NK-mediated regulatory function is also supported by the observation that ahigher number of bone marrow NK cells has been associated with a decreasedincidence of chronic GVHD after HLA identical sibling bone marrow transplantsin human.(17)Researches in 2002 and 2004 showed that this regulatory functioncan be indirect, through the interplay and molecular crosstalk with dendriticcells (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 theproduction of cytokines such as IL-2, IL-12, IL-15, IFN-a/b, and TNFa.(16) Theregulatory function of NK cells on adaptive immuneresponses appears also to bemediated through direct lysis of activated T cells (20,21). This pathway hasbeen postulated to play an important role in the generation of memory T cell repertoire.
Several recent observations suggest that certain subpopulations of NK cellspromote allograft tolerance via a cytolysis-dependent regulatory pathway (22–24).However, little is known about the effects of NK cells on donor T cells afterBMT. In 2010, Magali Noval Rivas et al showed that NK cells can regulatechronic GVHD by limiting recipient minor histocompatibility Ag (mHA)-drivenproliferation 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 immunesuppressivecytokines canprevent GvHD, it is established that pro-inflammatory cytokine production by NKcells can contribute to GvHD development. Xun et al. showed In a xenogeneicmodel that in vitro interleukin-2 (IL-2)-activated human NK cells producinginterferon-?(IFN-?) and tumor necrosis factor-?(TNF-?) were able to induceacute GVHD upon transfer into SCID mice (30, 31) What is now important about NK cells and its impact on GVHD is thatresearchers are looking for new ways to reduce GVHD with the help of thesecells, which we will continue to mention theseactivities.Cytokines also play a key role in the differentiation of NKcells. Interleukin (IL)-2, IL-15, and IL-21, are capable of inducing proliferationand 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 andmaintenance (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-12and IFN-?/? exert potent stimulatory effects on NK cells, and IL-12 and IL-18in combination is particularly effective in augmenting NK cell function (20, 21).IL-2 has also been shown to significantly activate NK cells, and adoptiveimmunotherapy of IL-2 activated NK cells after autologous BMT has been used inpatients with cancer with acceptable toxicities.(22) The predominant cytolytic targetsof 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 commonmechanism by which tumors and virus-infected cells can evade recognition by theT-cell receptor of cytolytic T cells, andNK cells.(24,25) Recently, NK cells were officially classified as theprototypical members of the group 1 innate lymphoid cells (ILCs), which aredefined by their capacity to secrete IFN-? but not type 2 cytokines (IL-4 andIL-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 ofNK-like T cells and antigen-experienced T cells that have upregulated severalNK cell markers.(28)Two major subsetsof NK cells are found in human subjects that can be distinguished by theirlevels of CD56 expression, namely CD56dim and CD56bright.(28) CD56dimNK cells are fully mature, make up approximately 90% of the NK cells inperipheral blood, and predominantly mediate cytotoxicity responses. Incontrast, CD56bright cells are more immature, make up approximately5% to 15% of total NK cells, and have been considered primarily as cytokineproducers while playing a limited role in cytolytic responses.
Although CD56brightNK cells are more efficient at producing cytokines overall, the CD56dimNK cells can also contribute significantly to early cytokine production becausethey comprise a significantly greater fraction of the total NK cell pool andcan more rapidly secrete cytokines.(29-31)